Lipoprotein a

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Apolipoprotein (a)
Properties of human protein
Mass / length primary structure 4529 amino acids
Identifier
Gene names LPA  ; Apo (a)
External IDs
Enzyme classification
EC, category 3.4.21. ,  Serine protease

Apolipoprotein B-100
Properties of human protein
Mass / length primary structure 4536 amino acids
Identifier
Gene name APOB
External IDs
Occurrence
Homology family APOB
Parent taxon Vertebrates

Lipoprotein (a) , Lp (a) for short, is a lipoprotein whose protein component consists of apolipoprotein (a) and apolipoprotein B-100. It is a component of blood lipids and its structure is very similar to LDL cholesterol . For cardiovascular complications such as heart attack or stroke , it should be viewed as an additional independent risk factor, especially if there are high levels in the blood. Mutations in APOB - gene can defective apoB-100 and this can cause rare hereditary Hypolipoproteinemia lead (FHBL) as well as hereditary ligands defect in apoB-100 (FDB). In conjunction with other defects, hypocholesterolemia can occur.

Characteristic

Lipoprotein (a) was first described in 1963 by the Norwegian doctor Berg and his colleagues as a lipoprotein associated antigen . With its molecular weight, it is very close to LDL cholesterol . The structure of lipoprotein (a), like LDL cholesterol, is one of the low-density lipoproteins (LDL) and, in addition to the component ApoB-100, which is also present in LDL cholesterol, it also has the glycoprotein Apo (a). Apo (a) is similar to plasminogen , which means that lipoprotein (a), in addition to its atherosclerotic potency, can also promote thrombosis and embolism .

Analogous to plasminogen, it can couple to its binding sites and thus prevent its thrombolytic activity. Lipoprotein (a) is a link between blood lipids and coagulation molecules in the blood. There is still very little reliable knowledge about its normal tasks in the organism. It has effects on wound healing and blood clotting like vitamin C and could therefore represent a physiological protective mechanism against the consequences of a vitamin C deficiency. According to the scientific literature, however, these relationships have not yet been definitively proven.

The plasma levels of lipoprotein (a) are predominantly genetically determined and therefore very stable. The lipoprotein (a) determination is not suitable as a screening parameter, but should be carried out in a targeted manner. If one of the following findings applies to a patient with a vascular disease and the LDL cholesterol is untreated or treated in the normal range, a lipoprotein (a) determination is recommended:

  • ≥ 2 cardiovascular events in the past 2 years.
  • Clinically and / or documented by imaging procedures, there is a progressive or recurrent cardiovascular disease despite effective treatment of other existing cardiovascular risk factors.
  • Cardiovascular complications before the age of 50 despite treatment of existing cardiovascular risk factors.
  • Familial burden for the occurrence of cardiovascular complications.

Lp (a) increase

Lipoprotein (a) plasma levels from 30 mg / dl are associated with an increasing cardiovascular risk and are considered to be elevated. Since the lipoprotein (a) molecules change in their mass depending on the plasma level, the lipoprotein (a) plasma level should now be given in nmol / L according to international agreement. A direct conversion is only possible approximately due to the change in mass. The lipoprotein (a) -mediated risk of vascular diseases ( coronary heart disease , myocardial infarction , stroke and arterial occlusive disease ) is increased by the interaction with other existing risk factors. But lipoprotein (a) can also be the primary determining risk factor in patients with early onset or particularly rapidly progressing vascular disease. Lipoprotein (a) accumulates in locations with existing vascular damage in the inner vascular wall of the arteries. The importance of lipoprotein (a) for coronary heart disease has been documented most extensively in large epidemiological studies.

The 2008 Copenhagen City Heart Study demonstrated that elevated lipoprotein (a) levels were predictive of the occurrence of heart attacks in the general population. Above the 90th percentile of lipoprotein (a) there was a 3 to 4-fold higher risk of myocardial infarction. Male subjects with high lipoprotein (a) and other cardiovascular risk factors had a 10-year risk of 35%. The increased risk also applies to patients on statin therapy . For female persons older than 65 years, however, a study found that Lp (a) does not represent an independent cardiovascular risk factor.

Therapy of Lp (a) elevation

The plasma levels of lipoprotein (a) are genetically determined, are independent of the levels of other blood lipids and cannot be influenced clinically by diet or lifestyle changes. During therapy with nicotinic acid preparations, an approximately 25% reduction can be achieved, which is not sufficient as the vascular disease progresses. The problem of flush side effects also limits long-term therapy in combination with the recently approved prostaglandin D 2 antagonist (inhibitor of flush symptoms). With a Rote-Hand-Brief on December 27, 2012, it was finally indicated that the drug Tredaptive (nicotinic acid / laropripant ) should no longer be prescribed for the therapy of lipoprotein (a) elevation. Lipid apheresis is currently the only way to effectively lower the lipoprotein (a) level. The use of lipid apheresis for the treatment of patients with isolated lipoprotein (a) elevation and progressive coronary heart disease that cannot be influenced therapeutically has been pursued as a therapeutic attempt in Germany since the early 1990s. The university hospitals in Berlin and Munich did pioneering work. The clinical successes were impressive, the number of patients remained very small. A four-year, multicenter prospective clinical study Pro (a) LiFe on 170 patients, completed in 2013, showed an average decrease of 78 percent in coronary events during the two-year phase of lipoprotein apheresis compared to the previous two years with lipid-lowering medication. However, this study has significant methodological weaknesses - it is a purely observational study, and the LDL-C lowering was clearly too low before the start of lipid apheresis. It can be postulated that with better pharmacological accompanying therapy, the effect would have been much smaller.

Lipid apheresis

The term lipid apheresis covers extracorporeal blood purification procedures carried out on an outpatient basis , which can eliminate blood lipids, in particular LDL cholesterol and lipoprotein (a), with the help of various physicochemical separation principles ( filtration , precipitation or adsorption of plasma or whole blood ).

With all the methods currently in routine use in Germany, it is possible to achieve the quality criterion of at least 60% lowering of LDL cholesterol per therapy session, with lipoprotein (a) 70% are achieved. The treatment takes place weekly to two weeks. Lipid apheresis is a therapy option in the treatment of severe hypercholesterolemia (increased LDL cholesterol) that does not respond adequately to medication , but it still has to be approved by health insurance companies in each individual case.

Takeover by the health insurance companies in Germany

Lipid apheresis is part of the step therapy for severe hypercholesterolemia ; reimbursement guidelines for statutory health insurance have existed in this regard since 1991 . In 1996, the consideration of the entire cardiovascular risk profile was added, with the explicit inclusion of lipoprotein (a). In the new version in 2003, lipoprotein (a) was denied an indication-based significance. Since then, patients have only been able to be treated after uncertain individual decisions by the health insurers or after taking legal action. After several years of public protests by those affected and the doctors treating them, the joint federal committee , the body that defines the list of benefits for statutory health insurance, revised its decision in 2008. The following indications for lipid apheresis have been approved and explained:

  • At the same time documented clinically and by imaging procedures, there is a progressive cardiovascular disease (coronary heart disease, peripheral arterial disease or cerebrovascular disease).
  • With the use of the established treatment methods it was not possible to stop the progression of the disease.
  • Lipoprotein (a) is greatly increased at> 60 mg / dl, the LDL cholesterol is in the normal range.
  • An expert committee carefully examined each individual case and made a positive recommendation for the use of lipid apheresis on the basis of an individual benefit-harm assessment.
  • Patients who are to receive Lp (a) apheresis should be asked whether or not they would like to participate in clinical studies to evaluate the benefits of Lp (a) apheresis.

Overall, according to G-BA guidelines, lipid apheresis should be used as the “last resort” in the event of a therapy-refractory course. The overall risk profile of the patient should be in the foreground when weighing up the indication. This empirical-pragmatic indication regulation is patient-friendly. The lipoprotein (a) blood level alone is not sufficient to indicate the need for lipid apheresis. The progression of cardiovascular disease clinically and imaging documented is an essential condition. As part of its resolution, the joint federal committee demanded the submission of further scientific results on the effectiveness of lipid apheresis in the case of lipoprotein (a) increase in parallel to the reimbursement.

Efficacy of lipid apheresis in the case of isolated lipoprotein (a) elevation

The effectiveness of lipid apheresis in the case of lipoprotein (a) elevation was analyzed in a retrospective study in Germany based on the multi-year course before and after the start of chronic lipid apheresis. The primary study parameter was the annualized rate of severe cardiovascular events (myocardial infarction, coronary intervention, coronary bypass surgery, sudden cardiac death ). The mean concentration of lipoprotein (a) before apheresis was initiated was 118 mg / dl. The mean trough level after initiation of lipid apheresis was 33 mg / dl, corresponding to a 72% reduction. The mean incidence of severe cardiovascular events in the patients was about 1 / year and increased exponentially with the duration of the illness in the observation period before the start of apheresis. If one compares the classification according to the Framingham Score , which defines the high risk of heart attack as> 20% in 10 years, it becomes clear that an extreme risk group was recorded. The mean rate of severe cardiovascular events during the observation period under apheresis was only 0.14 / year, corresponding to a statistically meaningful 86% reduction in the event rate . The rapid decline after initiation of lipid apheresis was remarkable. All lipid apheresis methods used were equivalent in this regard. These results confirm the assumption that increased lipoprotein (a) levels favor atherothrombotic complications and a progressive course of vascular disease, and that lowering the lipoprotein (a) level by means of lipid apheresis can prevent subsequent complications. The Pro (a) life study (Lipoprotein Apheresis in Patients With Maximally Tolerated Lipid-Lowering Therapy, Lipoprotein (a) -Hyperlipoproteinemia, and Progressive Cardiovascular Disease) was a prospective observational study on 170 patients nationwide in Germany. The results were published in Circulation in September 2013. The examined patients had a lipoprotein (a) value of> 60 mg / dl and they showed severe progressive cardiovascular disease with the maximum possible lipid-lowering medication (which, however, was not sufficient from today's perspective). After starting lipid apheresis, a reduction in cardiovascular events of> 80% was observed. The results of this study support the assumption that lipoprotein (a) is an independent risk factor for progressive cardiovascular disease if all other co-existing risk factors are treated as best as possible. A follow-up of the Pro (a) -LiFe study after five years showed a lasting effectiveness of regular lipid apheresis. During this period, no further increase in cardiovascular events could be determined. Since Pro (a) -LiFe is a purely observational study, the evidence for lipid apheresis is still low.

Lipoprotein (a) can be the primary determining risk factor in patients with early onset or particularly progressive vascular disease. The results so far on the effectiveness of lipid apheresis confirm that increased lipoprotein (a) levels favor atherothrombotic complications and a progressive course of the vascular disease, and that lowering the lipoprotein (a) level can prevent subsequent complications. The joint federal committee has thus translated the plausible use of lipid apheresis in the case of isolated lipoprotein (a) elevation into a reimbursement regulation of the statutory health insurance according to the best available evidence. Lipoprotein (a) should be included in the risk assessment in the event of familial stress, early onset of cardiovascular complications, and rapidly progressing vascular disease. The genetically determined value basically only needs to be determined once. Due to the not yet generally standardized measurement methods, laboratories with experience in lipid metabolism diagnostics should be chosen. Lipid apheresis is available for patients in whom lipoprotein (a) has been identified as the dominant factor in the severe course of their vascular disease. Further scientific results are required in order to scientifically substantiate the existing reimbursement regulation and to specify the indication.

Web links

Individual evidence

  1. ↑ UniProt P04114
  2. ↑ EA Enas, V. Chacko, A. Senthilkumar, N. Puthumana, V. Mohan: Elevated lipoprotein (a) - a genetic risk factor for premature vascular disease in people with and without standard risk factors: a review . In: Dis Mon . 52, No. 1, January 2006, pp. 5-50. doi : 10.1016 / j.disamonth.2006.01.002 . PMID 16549089 .
  3. ^ J. Danesh, R. Collins, R. Peto: Lipoprotein (a) and coronary heart disease. Meta-analysis of prospective studies . In: Circulation . 102, No. 10, September 2000, pp. 1082-5. PMID 10973834 .
  4. ↑ G. Luc, JM Bard, D. Arveiler et al. : Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study . In: Atherosclerosis . 163, No. 2, August 2002, pp. 377-84. PMID 12052486 .
  5. ↑ AR Sharrett, CM Ballantyne, SA Coady et al. : Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein (a), apolipoproteins AI and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study . In: Circulation . 104, No. 10, September 2001, pp. 1108-13. PMID 11535564 .
  6. ↑ S. Tsimikas, S. Kiechl, J. Willeit et al. : Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease: five-year prospective results from the Bruneck study . In: J. Am. Coll. Cardiol. . 47, No. 11, June 2006, pp. 2219-28. doi : 10.1016 / j.jacc.2006.03.001 . PMID 16750687 .
  7. ↑ PR Kamstrup, M. Benn, A. Tybjaerg-Hansen, BG Nordestgaard: Extreme lipoprotein (a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study . In: Circulation . 117, No. 2, January 2008, pp. 176-84. doi : 10.1161 / CIRCULATIONAHA.107.715698 . PMID 18086931 .
  8. ↑ Willeit P, Ridker PM, Nestel PJ, et al .: Baseline and on-statin treatment lipoprotein (a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet 2018; 392: 1311-1320. doi : 10.1016 / S0140-6736 (18) 31652-0 .
  9. ↑ AA Ariyo, C. Thach, R. Tracy: Lp (a) lipoprotein, vascular disease, and mortality in the elderly . In: N. Engl. J. Med. . 349, No. 22, November 2003, pp. 2108-15. doi : 10.1056 / NEJMoa001066 . PMID 14645638 .
  10. ↑ The effectiveness of lipoprotein apheresis in study proves Deutsches Ärzteblatt | Volume 110 | Issue 49 | December 6, 2013 | Accessed March 29, 2016
  11. ↑ J. Leebmann, E. Roeseler, U. Julius, F. Heigl, R. Spitthoever, D. Heutling, P. width, W. March, W. Lehmacher, A. Heibges, R. Bell; Pro (a) LiFe Study Group: Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein (a) -hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. . In: Circulation . 128, No. 24, December 2013, pp. 2567-2576. doi : 10.1161 / CIRCULATIONAHA.113.002432 . PMID 24056686 .
  12. ^ GR Thompson: Recommendations for the use of LDL apheresis . In: Atherosclerosis . 198, No. 2, June 2008, pp. 247-55. doi : 10.1016 / j.atherosclerosis.2008.02.009 . PMID 18371971 .
  13. ↑ Federal Ministry of Health: Announcement of a resolution of the Federal Joint Committee on a change to the guideline methods of statutory health care: Apheresis in the case of isolated Lp (a) increase. From June 19, 2008. BAnz. No. 138, September 11, 2008, p. 3 321.
  14. ^ BR Jaeger, Y. Richter, D. Nagel et al. : Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein (a) levels and prevent major adverse coronary events . In: Nat Clin Pract Cardiovasc Med . 6, No. 3, March 2009, pp. 229-239. doi : 10.1038 / ncpcardio1456 . PMID 19234501 .
  15. ↑ J. Leebmann, E. Roeseler, U. Julius, F. Heigl, R. Spitthoever, D. Heutling, P. width, W. March, W. Lehmacher, A. Heibges, R. Bell; Pro (a) LiFe Study Group: Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein (a) -hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. . In: Circulation . 128, No. 24, December 2013, pp. 2567-2576. doi : 10.1161 / CIRCULATIONAHA.113.002432 . PMID 24056686 .
  16. ^ E. Roeseler, U. Julius, F. Heigl, R. Spitthoever, D. Heutling, P. Breitenberger, J. Leebmann, W. Lehmacher, PR Kamstrup, BG Nordestgaard, W. Maerz, A. Noureen, K. Schmidt , F. Kronenberg, A. Heibges, R. Klingel; Pro (a) LiFe-Study Group: Lipoprotein apheresis for lipoprotein (a) -associated cardiovascular disease: Prospective 5 years of follow-up and apolipoprotein (a) characterization. . In: Arterioscler Thromb Vasc Biol. . 36, No. 9, September 2016, pp. 2019–2027. doi : 10.1161 / ATVBAHA.116.307983 . PMID 27417585 .