Lipoprotein(a) – the Deadliest Cholesterol of All

  • Lipoprotein(a) (always pronounced Lp-little-a) is a strong, putative, and causal risk factor for heart attack and stroke.1, 2 Lp(a) is a genetic variant of LDL (low-density lipoprotein) particle with one molecule of apolipoprotein B100 (apoB) and an additional protein, apo(a), attached via a disulphide bond.3
  • A systemic review and meta-analysis of 67 prospective studies including 181,683 individuals has confirmed a 2-fold risk of CAD (coronary artery disease) independent of all modifiable risk factors.3 This effect is substantially higher in individuals with previous CAD.
  • Although genetically determined, prescription niacin is highly effective in lowering Lp(a) and reducing cardiovascular risk. People with elevated Lp(a) require intensive medical management to avoid cardiovascular catastrophe at a very young age.1, 4 Lp(a) is one of the strongest biological markers for premature heart disease.
  • Lp(a) concentrations are largely genetically determined through autosomal-dominant transmission.4 Lp(a) levels are high in people with a family history of early heart disease. Stable Lp(a) level is reached by age two and remains at that level throughout life. It does not fall with exercise, but rises if you eat a lot of trans fats, as most Indians do.
  • Lp(a) is therefore strongly associated with premature, severe cardiovascular disease that often leads to massive heart attacks and strokes at a very young age.4 Childhood levels of Lp(a) are a better predictor and marker for future CAD in young adult life than any other lipoproteins.5-7
  • Racial differences in blood Lp(a) levels are present and expressed at birth. Expression of the racial profile of Lp(a) at birth was studied in the cord blood of 542 male and 468 female newborns from three ethnic groups of Singapore. Lp(a) levels in newborns were found to be independent of the infant’s birth weight and sex but were significantly influenced by race. Indian newborns had significantly higher blood levels of Lp(a) and Chinese newborns had the lowest Lp(a) levels at birth (Figure 004).8
  • High levels of Lp(a) are often found in people with family history or personal history of premature heart disease, stroke or repeat coronary angioplasty, stent or bypass surgery.4
  • Lp(a) is a strong independent risk factor for premature CAD in many populations including Europids, Chinese, and Japanese and Asian Indians and to a less extent in blacks.9-12 Lp(a) plays a crucial role in the heighted risk for malignant CAD in young Asian Indians and other South Asians.13-16
  • High Lp(a) levels confer a 2-4-fold risk of first or recurrent heart attack or stroke.4 Lp(a) levels >30 mg/dL is an independent risk factor for premature CAD with risk comparable in magnitude to a total cholesterol level of >240 mg/dL or an HDL-C level of <35 mg/dL.17 The risk increases to 25-fold in those who have all three of these lipid abnormalities.4
  • Elevated levels of Lp(a) has a magnifying effect on many traditional and emerging risk factors. In people with high levels of Lp(a), the cardiovascular risk is increased 3-fold in the absence of other risk factors, 8-fold with low HDL-C, and 12-fold with high LDL-C. The risk is increased up to 122-fold, depending upon the number and severity of other concomitant risk factors (such as diabetes, obesity, smoking, high blood pressure, high cholesterol, and sedentary lifestyle).4 (see Multiplicative Effects of Lp(a))
  • A high level of Lp(a) is strongly associated with rapid restenosis (re-narrowing of the artery) following coronary angioplasty, with or without stent placement and bypass surgery. The risk is particularly high in people who also have low HDL as most Indians do.
  • Elevated Lp(a) levels are found in 35-42% of Indians worldwide, a level second only to that of blacks. Strikingly, Lp(a) is particularly dangerous among Indians due to common occurrence of high TC/HDL ratio. (see Lp(a) among Asian Indians).4 
  • Although the relationship of Lp(a) to CAD is continuous and graded, a level of 30 mg/dL has long been  considered the threshold.18-20 The new NHLBI recommendations require Lp(a) to be reported in nmol/l. A value of 75nmol/l is arbitrarily set as the cut point, but 50 nmol/l may be the appropriate cut-point, particularly for Indians.4
  • Cholesterol-lowering statins do not lower Lp(a) directly, but they help reduce the risk since Lp(a) is more harmful when working in concert with high LDL-C.4, 21 Prescription niacin lowers Lp(a) safely and effectively and is recommended for all patients with high levels according to the recent European guidelines.1 Two grams a day reduces it by about 25%, and 4 grams by almost 40%.4  (See Lp(a) Treatment)
  • The term “deadly cholesterol” may be used to describe Lp(a) and to distinguish it from the  “good cholesterol”  or HDL, the “bad cholesterol” or LDL,  and the “ugly cholesterol” or triglycerides.
  • Lp(a) is seldom tested or treated in the vast majority of cases because most insurance companies do not pay for the tests and individuals are unwilling to spend their own money for one reason or another.

1. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. Oct 21 2010.

2. Erqou S., Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. Jul 22 2009;302(4):412-423.

3. Genser B, Dias KC, Siekmeier R, Stojakovic T, Grammer T, Maerz W. Lipoprotein (a) and risk of cardiovascular disease–a systematic review and meta analysis of prospective studies. Clin Lab. 2011;57(3-4):143-156.

4. Enas EA, Chacko V, Senthilkumar A, Puthumana N, Mohan V. Elevated lipoprotein(a)–a genetic risk factor for premature vascular disease in people with and without standard risk factors: a review. Dis Mon. Jan 2006;52(1):5-50.

5. Enas EA. Prevention and treatment of coronary artery disease. JAPI. 1997;45:309-315.

6. Wilcken DE, Wang XL, Dudman NP. The relationship between infant and parent Lp(a) levels. Chem Phys Lipids. 1994;67-68:299-304.

7. Rifai N, Heiss G, Doetsch K. Lipoprotein(a) at birth, in blacks and whites. Atherosclerosis. Feb 1992;92(2-3):123-129.

8. Low PS, Heng CK, Saha N, Tay JS. Racial variation of cord plasma lipoprotein(a) levels in relation to coronary risk level: a study in three ethnic groups in Singapore. Pediatr Res. 1996;40(5):718-722.

9. Rhoads GG, Dahlen G, Berg K, Morton NE, Dannenberg AL. Lp(a) lipoprotein as a risk factor for myocardial infarction. Jama. 1986;256(18):2540-2544.

10. Uterman G. Lipoprotein(a). In: Scriver CR BA, Sly WS, Valle D, ed. The Metabolic and Molecular Basis of Inherited Disease. New York, NY: McGraw Hill Inc; 1995:1887-1912.

11. Woo J, Lau E, Lam CW, et al. Hypertension, lipoprotein(a), and apolipoprotein A-I as risk factors for stroke in the Chinese. Stroke. Feb 1991;22(2):203-208.

12. Sandholzer C, Hallman DM, Saha N, et al. Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups. Hum Genet. 1991;86(6):607-614.

13. Khunti K, Samani NJ. Coronary heart disease in people of south-Asian origin. Lancet. Dec 11 2004;364(9451):2077-2078.

14. Enas EA. Why is there an epidemic of malignant CAD in young Indians? Asian J Clin Cardiol. 1998;1:43-59.

15. Enas EA. Lipoprotein(a) is an important genetic risk factor for coronary artery disease in Asian Indians. Am  J  Cardiol. 2001;88:201-202.

16.  Enas EA, Mehta J. Malignant coronary artery disease in young Asian Indians: thoughts on pathogenesis, prevention, and therapy. Coronary Artery Disease in Asian Indians (CADI) Study. Clin Cardiol. Mar 1995;18(3):131-135.

17. Bostom AG, Cupples LA, Jenner JL, et al. Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger. A prospective study. Jama. 1996;276(7):544-548.

18. von Eckardstein A, Schulte H, Cullen P, Assmann G. Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk. J Am Coll Cardiol. 2001;37(2):434-439.

19. Hoogeveen RC, Gambhir JK, Gambhir DS, et al. Evaluation of Lp[a] and other independent risk factors for CHD in Asian Indians and their USA counterparts. J Lipid Res. 2001;42(4):631-638.

20.  Enas EA, Senthilkumar A. Conquering the epidemic of coronary artery disease among Indians: Crucial role of cardiologists. Cardiology Today. 2001;5:282-294.

21. Enas EA. How to Beat the Heart Disease Epidemic among South Asians: A Prevention and Management Guide for Asian Indians and their Doctors. Downers Grove: Advanced Heart Lipid Clinic  USA; 2010.

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