German Haemapheresis Centre

and

German Apheresis Research Centre

Atherogenesis by Lp(a)

On the one hand the potential significance of elevated Lp(a) values for the development of atherosclerosis is not in dispute anymore, on the other hand a differentiated examination is necessary.

Therapy of elevated Lp(a) levels in the plasma

Generally, a plasma level of above 30 mg/dl is accepted as a borderline value. Higher values are potentially pathogen with regard to a premature arteriosclerosis. Even if the exact circumstances of this pathogenicity are not examined sufficiently, indications for treatment still exist.

Drug therapy for a reduction of elevated Lp(a) is not yet available or insufficient (e.g. nicotine acid, fibrates). In experiments with high doses of ascorbic acid (at least 1 g/d) only few not well documented cases showed a reduction of elevated Lp(a) levels.

An elimination of other risk factors is generally recommended. A reduction of LDL-cholesterol levels to as low values as possible is recommended particularly. Such recommendations are not considered as a therapy, but obviously as a preventive step.

Out of the extracorporeal procedures the highly selective Lp(a)-apheresis from the company Pocard, Moscow, is the most effective procedure. With repetitive-cycling loading and desorption of adsorbers it enables to reach a target value of 30 mg/dl after treatment even in patients with high pretreatment levels. Because of the possibility to reuse the system for at least 100 times this procedure is very cost-effective as treatment costs are reduced with every additional treatment.

Other extracorporeal procedures may reduce Lp(a) levels as well, but in patients with high Lp(a) pretreatment levels target values may not be achieved after treatment. Here we prefer repetitive-cycling procedures like the original LDL-apheresis in contrast to other procedures like precipitation with heparin, filtration or whole blood adsorption.

Lp(a)-elevations in the plasma can reach from mildly elevated (e.g. 40 mg/dl) up to severely elevated levels (e.g. in a burdened family > 600 mg/dl) to our knowledge. The importance of an extracorporeal procedure is not only dependent on the potential to lower the values with regard to pretreatment levels but also on the accessibility of an optimal target value. Because of a fast increase of Lp(a) values a weekly treatment is compulsory. With regard to 25 years of experience with the original LDL-apheresis we commit on a target value of below 30 mg/dl after treatment. This should not only lead to a decelerated proceeding of the disease expecting cardiological or cardiosurgical steps to be taken out at an older age, but should also lead to a complete persistance. Due to medical reasons and reduction of complications this procedure is of great advantage.

Indications for extracorporeal LDL-elimination

For diagnosis three different aspects deserve special attention:

1. The single elevation of Lp(a)
2. The elevation of Lp(a) together with an elevation of LDL-cholesterol
3. The elevation of Lp(a) in combination with other general risk factors


1. The single elevation of Lp(a)

Due to our knowledge the single elevation of Lp(a) a priori is no indication for an extracorporeal Lp(a)-elimination. We have seen several patients over 50 years with values up to 600 mg/dl or above without signs of a premature atherosclerosis. Therefore a single elevation of Lp(a) without clinical symptoms is no indication for Lp(a)-apheresis or other extracorporeal procedures eliminating Lp(a) also.

For patients with Lp(a)-elevation without symptoms we recommend an extensive clinical, cardiological and angiological examination and a yearly check-up, if findings are negative. If a premature atherosclerosis can not be detected we recommend further yearly clincal, cardiological and angiological examinations holding back extracorporeal treatment. For patients with signs of progression of a premature atherosclerosis a Lp(a)-elimination or preferably Lp(a)-apheresis is indicated.

Also for symptomatic patients with the presence of complications such as coronary heart disease, myocardial infarction or atherosclerotically induced compromised perfusion, which can be proved by objective, pathological, radiological procedures, extracorporeal Lp(a)-elimination is induced.

2. The elevation of Lp(a) together with an elevation of LDL-cholesterol

LDL-cholesterol is a major risk factor. The LDL-elimination is indicated in patients suffering from familial hypercholesterolaemia combined with the existance of heritage, coronary heart disease or atherosclerosis of other areas in the vascular system and side effects from drug therapy, leading to an insufficient removal towards the target level. To our knowledge the target values after treatment of < 50 mg/dl LDL-cholesterol and < 100 mg/dl total cholesterol presently have been proved. These targets, which have been recommended by our institution for several years, are corresponding to the latest guidelines of the American Cholesterol Educational Program (ACEP III) and can most likely be achieved with repetive-cycling systems, while single-use systems -regularly recommended by industry- frequently not achieve the target values. The commitment to a removal of 60 % is not keeping with the times as pretreatment levels are different in patients.

Over two third of our patients with familial hypercholesterolaemia (n = 31) additionally show an elevation of Lp(a) of different dimension. In patients with mild to moderate elevation a sufficient reduction of Lp(a) to the target level of approximately 30 mg/dl can be achieved with repetitive-cycling LDL-elimination systems.

In patients with higher pretreatment levels a reduction with technical devices for the effective elimination of LDL-cholesterol can be insufficient. In these cases a combination of an anti-Apoprotein B- with a Lp(a)-apheresis-column has to be kept in mind.

3. The elevation of Lp(a) in combination with other general risk factors

In cases where -beside an elevation of Lp(a)- other common and generally accepted risk factors for a premature atherosclerosis (smoking, poorly adjusted diabetes mellitus or inadequately treated hypertension) are present, an extracorporeal Lp(a)-elimination can be justified, if additional risk factors have been removed prior to apheresis.

3.)
4.)
5.)
6.)
7.) Atherogenicity
7.1) Lp(a) as an isolated risk factor for premature atherosclerosis
7.2) Lp(a) as an independent risk factor and as a risk factor in combination with other risk factors for premature atherosclerosis
7.3) Lp(a) as an independent risk factor and as a risk factor in combination with other risk factors for premature atherosclerosis (especially reduced HDL-cholesterol)
7.4) Lp(a) as a risk factor in combination with other risk factors for premature atherosclerosis
8.) Lp(a) and stroke
9.) Lp(a) and aneurysm
10.) Lp(a) and diabetes
11.) Lp(a) and nephropathy
12.) Lp(a) and renal transplant
13.) Lp(a) and hypertension
14.) Lp(a) and pulmonary hypertension
Literaturhinweise bitte aus deutscher Version übernehmen

Literature

1.) Overlook

Kraft HG, Lingenhel A, Raal FJ, Hohenegger M, Utermann G.
Lipoprotein(a) in homozygous familial hypercholesterolemia.
Arterioscler Thromb Vasc Biol. 2000 Feb;20(2):522-8

Kronenberg F, Kronenberg MF, Kiechl S, Trenkwalder E, Santer P, Oberhollenzer F, Egger G, Utermann G, Willeit J.
Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study.
Circulation. 1999 Sep 14;100(11):1154-60

Kronenberg F, Steinmetz A, Kostner GM, Dieplinger H.
Lipoprotein(a) in health and disease.
Crit Rev Clin Lab Sci. 1996 Dec;33(6):495-543. Review

Kostner KM, Kostner GM.
The Physiological Role of Lipoprotein (a).
Drug News Perspect. 2002 Mar;15(2):69-77

Kostner KM, Kostner GM.
Lipoprotein(a): still an enigma?
Curr Opin Lipidol. 2002 Aug;13(4):391-6. Review

 

2.) Catabolism

Kronenberg F, Trenkwalder E, Lingenhel A, Friedrich G, Lhotta K, Schober M, Moes N, Konig P, Utermann G, Dieplinger H.
Renovascular arteriovenous differences in Lp[a] plasma concentrations suggest removal of Lp[a] from the renal circulation.
J Lipid Res. 1997 Sep;38(9):1755-63

 

3. ) Selective techniques of elimination

Pokrovsky SN, Adamova IYu, Afanasieva OY, Benevolenskaya GF.
Immunosorbent for selective removal of lipoprotein (a) from human plasma: in vitro study.
Artif Organs. 1991; 15 (2): 136 - 140

Pokrovsky SN, Sussekov AV, Afanasieva OI, Adamova IY, Lyakishev AA, Kukharchuk VV.
Extracorporeal immunoadsorption for the specific removal of lipoprotein (a) (Lp(a) apheresis): preliminary clinical data.
Chem Phys Lipids. 1994; 67 - 68: 323 - 330

Pokrovsky SN, Ezhov MV, Il'ina LN, Afanasieva OI, Sinitsyn VY, Shiriaev AA, Akchurin RS.
Association of lipoprotein(a) excess with early vein graft occlusions in middle-aged men undergoing coronary artery bypass surgery.
J Thorac Cardiovasc Surg. 2003; 126 (4): 1071 - 1075

 

4.) Genetic, genetic architecture, structure

Utermann G, Haibach C, Trommsdorff M, Kochl S, Lingenhel A, Abe A, Kraft HG.
Genetic architecture of the atherogenic lipoprotein(a).
Ann N Y Acad Sci. 1995 Jan 17;748:301-11; discussion 311-2. No abstract available

Kostner GM, Wo X, Frank S, Kostner K, Zimmermann R, Steyrer E.
Metabolism of Lp(a): assembly and excretion.
Clin Genet. 1997 Nov;52(5):347-54

Ogorelkova M, Kraft HG, Ehnholm C, Utermann G.
Single nucleotide polymorphisms in exons of the apo(a) kringles IV types 6 to 10 domain affect Lp(a) plasma concentrations and have different patterns in Africans and Caucasians.
Hum Mol Genet. 2001 Apr 1;10(8):815-24.

5.) Methods of measuring

Scholtz CL, Lingenhel A, Hillermann R, Stander IA, Kriek JA, Marais MP, Odendaal HJ, Kraft HG, Utermann G, Kotze MJ.
Lipoprotein(a) determination and risk of cardiovascular disease in South African patients with familial hypercholesterolaemia.
S Afr Med J. 2000 Apr;90(4):374-8.

Tate JR, Berg K, Couderc R, Dati F, Kostner GM, Marcovina SM, Rifai N, Sakurabayashi I, Steinmetz A.
International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Standardization Project for the Measurement of Lipoprotein(a). Phase 2: selection and properties of a proposed secondary reference material for lipoprotein(a).
Clin Chem Lab Med. 1999; 37 (10): 949 - 958.

Kostner GM, Ibovnik A, Holzer H, Grillhofer H.
Preparation of a stable fresh frozen primary lipoprotein[a] (Lp[a]) standard.
J Lipid Res. 1999; 40 (12): 2255 - 2263

Tate JR, Rifai N, Berg K, Couderc R, Dati F, Kostner GM, Sakurabayashi I, Steinmetz A.
International Federation of Clinical Chemistry standardization project for the measurement of lipoprotein(a). Phase I. Evaluation of the analytical performance of lipoprotein(a) assay systems and commercial calibrators.
Clin Chem. 1998 ; 44 (8 Pt 1):1629 - 1640

Kostner GM, Steinmetz A.
Standardization of Lp(a) measurements.
Clin Genet. 1997; 52 (5): 393 - 397

6.) Coagulation

Caplice NM, Panetta C, Peterson TE, Kleppe LS, Mueske CS, Kostner GM, Broze GJ Jr, Simari RD.
Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis.
Blood. 2001 Nov 15;98(10):2980-7

Buechler C, Ullrich H, Ritter M, Porsch-Oezcueruemez M, Lackner KJ, Barlage S, Friedrich SO, Kostner GM, Schmitz G.
Lipoprotein (a) up-regulates the expression of the plasminogen activator inhibitor 2 in human blood monocytes.
Blood. 2001 Feb 15;97(4):981-6

Christ G, Kostner K, Zehetgruber M, Binder BR, Gulba D, Huber K.
Plasmin activation system in restenosis: role in pathogenesis and clinical prediction?
J Thromb Thrombolysis. 1999 Jun;7(3):277-85. Review

 

7.) Atherogenität

7.1 ) Lp(a) als isolierter Risikofaktor vorzeitiger Atherosklerose

Hoefler G, Harnoncourt F, Paschke E, Mirtl W, Pfeiffer H, Kostner GM
Lipoprotein Lp(a). A rsik factor for myocardial infarction.
Arteriosclerosis 1988; 8 ( 4 ): 398 - 401

Sandkamp M, Funke H, Schulte H, Kohler E, Assmann G
Lipoprotein (a) is an independent risk factor for myocardial infarction at a young age.
Clin Chem 1990; 36 (1): 20 - 23

Watts, GF, Kearney EM, Taub NA Slavin BM
Lipoprotein (a) as an independent risk factor for myocardial infarction in patients with common hypercholesteroaemia
J. Clin Pathol. 1993; 46 (3): 267 - 70

Cantin B, Gagnon F, Moorjani S, Despres JP Lamarche B, Lupien PJ, Dagenais DR
Is lipoprotein (a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study.
J Am Coll Cardiool 1998; 32 (4): 1132 - 1134

Fujino A, Watanabe T, Kunii H, Yamaguchi N, Yoshinari K, Watanabe Y, Mutou M, Ishikawa S, Ogyuu A, Ashikawa K, Maruyama Y
Lipoprotein (a) is a potential coronary risk factor
Jpn Circ J 2000; 64 ( 1): 51 – 56

Price JF, Lee AJ, Rumley A, Lowe DG, Fowkes FG
Lipoprotein (a) and development of intermittent claudication and major cardiovascular events in men and Women: The Edinburgh Artery Study
Atherosclerosis 2001; 157 (1): 241 – 249

Serdar A, Yesilbursa D, Serdar Z
Lipoprotein (a) as a risk factor for coronary artery disease in women and elderly patients
Anadolu Kardiyol Derg. 2001; 1(4): 259 – 263 AXV – XVI

Hubacek JA, Stavek P. Pit’ha J, Skodova Z, Poledne R
Plasma level of Lp(a) in patients with myocardial infarct is not controlled by the apolipoprotein E gene polymorphism
Cas Lek Cesk 2001; 140 (11): 332 – 334

7.2 ) Lp(a) als unabhängiger Risikofaktorund als Risikofaktor in Kombination mit anderen Risikofaktoren vorzeitiger Atherosklerose

Dahlen GH, Stenlund H
Lp(a) lipoprotein is a major risk factor for cardiovascular disease:Pathogenic mechanisms and clinical significance.
Clin Genet 1997; 562 ( 5 ): 272 – 280

Bostom AG, Cupples LA, Jenner JL, Ordovas JM, Seman LJ, Wilson PW Schaefer EJ, Castelli WP

Elevated plasm lipoprotein (a) and coronary heart disease in men aged 55 years and younger. A prospective study.

JAMA 1996; 276 ( 7 ):544 – 548

Luc G, Bard JM, Arveiler D, Ferrieres J, Evans A, Amouyel P, Fruchart JC, Ducimetiere P, PRIME Study Group
Lipoprotein (a) as an predictor of coronary heart disease: The Prime Study
Atherosclerosis 2002; 163 ( 2 ): 377 – 384

Seed M, Ayres KL, Humphries SE, Miller GJ
Lipoprotein (a) as a predictor of myocardial infarction in middle-aged men
Am J Med 2001; 110 ( 1 ): 71 – 72

7.3 ) Lp(a) als unabhängiger Risikofaktor und als Risikofaktor in Kombination mit anderen Risikofaktoren vorzeitiger Atherosklerose ( insbesondere erniedrigtes HDL – Cholesterin)

Hopkins PN, Hunt SC, Sachreiner PJ, Eckfeldt JH, Borecki IB, Ellison CR, Williams RR, Siegmund KD
Lipoprotein (a) interactions with lipid and non-lipid risk factors in patients with early onset coronary artery disease: Results from the NHLBI Family Heart Study.
Atherosclerosis 1998; 141 ( 2 ): 333 – 345

Lingenhel A, Kraft HG, Kotze M, Peeters AV, Kronenberg F, Kruse R, Utermann G.
Concentrations of the atherogenic Lp(a) are elevated in FH.
Eur J Hum Genet. 1998 Jan;6(1):50-60

7.4) Lp(a) als Risikofaktor in Kombination mit anderen Risikofaktoren vorzeitiger Atherosklerose

Adlouni A, el Messal M, Ghalim N, Saile R
Apolipoproteins and lipoprotein particles in Moroccan patients with previous myocardial infarction.
Int J Clin Lab Res 1997; 27 ( 4 ): 247 -252

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

Solfrizzi V, Panza F, Colacicco AM, Capurso D, D’Introno A, Torres F, Baldassare G, Capurso A
Relation of lipoprotein (a) as coronary risk factor to type 2 diabetes mellitus and low-density lipoprotein cholesterol in patients > or = 65 years of age (The Italian Longitudinal Study on Aging, ILSA)
Am J Cardiol 2002; 89 ( 7 ):825 – 829

Cantin B, Despres JP, Lamarche B, Moorjani S, Lupien PJ, Bogaty P, Bergeron J, Dagenais GR
Association of fibrinogen ans lipoprotein (a) as a coronary heart disease risk factor in men (The Quebec Cardiovascular Study)

Am J Cardiol 2002; 89 ( 6 ): 662 – 666

 

8.) Lp(a) und Apoplex

Christopher R, Kailasanatha KM, Nagaraja D, Tripathi M
Case-control study of serum lipoprotein (a) and apolipoproteins A-I and B in stroke in the young.
Acta Neurol Scan 1996; 94 ( 2 ): 127 – 130

Cao GF, Yang QD, Liu YH, Xu HW, Xia J
Lipoprotein (a) and cerebral infarction in young adults
Zhonghua Liu Xing Bing Xue Za Zhi 2003; 24 ( 5 ): 397 – 400

9. ) Lp(a) und Aneurysma

Schillinger M, Domanovits H, Ignatescu M, Exner M, Bayegan K, Sedivy R, Polterauer P, Laggner AN, Minar E, Kostner K.
Lipoprotein (a) in patients with aortic aneurysmal disease.
J Vasc Surg. 2002 Jul;36(1):25-30.

10.) Lp(a) und Diabetes

Shi H, Fang J, Yang X, Shen Z, Zhu X.
Lipoprotein (a) concentration and apolipoprotein (a) phenotype in subjects with type 2 diabetes mellitus.
Chin Med J (Engl). 1998 Nov;111(11):1013-7

Kronenberg F, Auinger M, Trenkwalder E, Irsigler K, Utermann G, Dieplinger H.
Is apolipoprotein(a) a susceptibility gene for type I diabetes mellitus and related to long-term survival?
Diabetologia. 1999 Aug;42(8):1021-

 

11.) Lp(a) und Nierenerkrankungen

Kostner KM, Clodi M, Bodlaj G, Watschinger B, Horl W, Derfler K, Huber K.
Decreased urinary apolipoprotein (a) excretion in patients with impaired renal function.
Eur J Clin Invest. 1998 Jun;28(6):447-52

Cauza E, Kletzmaier J, Bodlaj G, Dunky A, Herrmann W, Kostner K.
Relationship of non-LDL-bound apo(a), urinary apo(a) fragments and plasma Lp(a) in patients with impaired renal function.
Nephrol Dial Transplant. 2003 Aug;18(8):1568-72

Kronenberg F, Trenkwalder E, Sturm W, Kathrein H, Konig P, Neyer U, Grochenig E, Utermann G, Dieplinger H.

LDL-unbound apolipoprotein(a) and carotid atherosclerosis in hemodialysis patients.
Clin Genet. 1997 Nov;52(5):377-86

Kronenberg F, Utermann G, Dieplinger H.
Lipoprotein(a) in renal disease.
Am J Kidney Dis. 1996 Jan;27(1):1-25. Review

Kronenberg F, Konig P, Neyer U, Auinger M, Pribasnig A, Lang U, Reitinger J, Pinter G, Utermann G, Dieplinger H.
Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.
J Am Soc Nephrol. 1995 Jul;6(1):110-20.

Kostner KM, Jansen M, Maurer G, Derfler K.
LDL-apheresis significantly reduces urinary apo(a) excretion.
Eur J Clin Invest. 1997 Jan;27(1):93-5.

12.) Lp(a) und Nierentransplantation

Kerschdorfer L, Konig P, Neyer U, Bosmuller C, Lhotta K, Auinger M, Hohenegger M, Riegler P, Margreiter R, Utermann G, Dieplinger H, Kronenberg F.

Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.
Atherosclerosis. 1999 Jun;144(2):381-91

 

13.) Lp(a) und Hypertonie

Sechi LA, Kronenberg F, De Carli S, Falleti E, Zingaro L, Catena C, Utermann G, Bartoli E.

Association of serum lipoprotein(a) levels and apolipoprotein(a) size polymorphism with target-organ damage in arterial hypertension.
JAMA. 1997 Jun 4;277(21):1689-95.

14.) Lp(a) und pulmonale Hypertonie

Ignatescu M, Kostner K, Zorn G, Kneussl M, Maurer G, Lang IM, Huber K.
Plasma Lp(a) levels are increased in patients with chronic thromboembolic pulmonary hypertension.
Thromb Haemost. 1998 Aug;80(2):231-2

 

This selection of literature reference may be incomplete.