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Clin Res Cardiol Suppl (2019) (Suppl) 14:1–4 https://doi.org/10.1007/s11789-019-00100-9 EDITORIAL 1 2 K. P. Mellwig ·A.Vogt © The Author(s) 2019 Lipoprotein(a) (LP(a))—discovered by Kare Berg in Kringles are characterized by 2–40 repeats creating at 1963—is of increasing importance in clinical routine as re- least 30 polymorphous isoforms of Apo(a), which are dif- ﬂected by the ESC/EAS Guidelines for the Management of ferent in terms of size and mass. Number and qualitative Dyslipidaemias and the recent AHA Guideline [2, 3]. These composition of kringle domains determine the atherogene- guidelines provide detailed recommendations for screening ity of Lp(a). The large isoforms with more kringle repeats and lipid analyses in the assessment of cardiovascular risk. seem to be less atherogenous than the smaller ones . A consensus paper of the European Society of Cardiology summarizes basic principles, background as well as diag- nostic and therapeutic principles . Synthesis and metabolism Apoprotein(a) is synthesized in the liver exclusively . Structure—physiochemical characteristics How much Apo(a) is produced by the liver depends on the LPA gene and its amount remains more or less constant LP(a) is a lipid protein complex with a structure compared during a person’s lifetime. As Lp(a) in males rises only to to that of LDL (low density lipoprotein). Another apopro- a minor extent with increasing age, this parameter has to be tein, glycoprotein apoprotein(a) (Apo(a)) is bonded to the determined only once in a lifetime. In women however, the apoprotein B-100 (Apo B-100) of the LDL cholesterol via analysis should be done before and after menopause, as the a disulphide bridge . Lp(a) level might markedly increase during menopause. It The presence of Apo(a) impairs the bond between Lp(a) is quite unclear where Lp(a) is produced, most probably on and the LDL receptor. An independent Lp(a) receptor has the surface of hepatocytes or in plasma. not been identiﬁed so far. Corresponding to the LDL choles- Catabolism of Lp(a) is independent of a functioning LDL terol (LDL-C), the Lp(a) molecule is coated by a layer of receptor . The kidney seems to have a speciﬁc binding simple phospholipids, free cholesterol, and apoproteins. Its capacity for Lp(a) . A reduced glomerular ﬁltration rate core consists of triglycerides and esteriﬁed cholesterol . (GFR) may lead to an increase in plasma concentration of Due to its structural similarity, Lp(a) competes with plas- Lp(a). Other factors are hypothyreosis or an acute phase minogen for bindings sites on endothelial cells thus block- reaction (e. g. acute myocardial infarction). Oestrogen ther- ing the development of plasmin . This leads to a de- apy, pregnancy or aspirin uptake cause a non-signiﬁcant or lay of ﬁbrinolysis. Similar to plasminogen, Apo(a) contains relevant reduction . a kringle domain . Genetics This article is part of the special issue “Lp(a) – Update 2018” Apo(a) is encoded by a gene on chromosome 6q26-27 K. P. Mellwig firstname.lastname@example.org . Lp(a) plasma concentration is controlled by the Lp(a) gene locus; polymorphisms of the Apo(a) kringle IV-2 re- Klinik für Allgemeine und Interventionelle peats are responsible for the differences in plasma level. Of Kardiologie/Angiologie, Herz- und Diabeteszentrum 48 single nucleotide polymorphisms (SNPs) in the Lp(a) NRW, Universitätsklinik, Ruhr-Universität Bochum, gene region, seven SNPs show a signiﬁcant association with Georgstr. 11, 32545 Bad Oeynhausen, Germany coronary heart disease . The frequently used but slightly Medizinische Klinik und Poliklinik IV, Klinikum der arbitrary normal value of <30 mg/dl (1.6 mmol/l) is based Universität München, Ziemssenstr. 1, 80336 Munich, Germany on data which show that with an increasing value the car- K 2 K. P. Mellwig, A. Vogt diovascular risk increases without a given threshold value Registry data show that the degree of aortic valve steno- . ESC recommends a threshold value of <50 mg/dl (80th sis rises with increasing Lp(a) levels . percentile) . Cerebrovascular and peripheral vascular disease, abdominal Thrombogenous and atherogenous characteristics aortic aneurysm In blood coagulation Lp(a) is the opponent of plasmino- Lp(a) is also discussed to be an independent risk factor for gen—the inactive preliminary enzyme stage of plas- cerebrovascular diseases. Particularly in young patients suf- min—which resolves ﬁbrin clots. Lp(a) competes with fering from an apoplectic insult Lp(a) might be a causative plasminogen for the binding sites on endothelial cells thus factor . Furthermore, Lp(a) seems to be a predictor for blocking plasmin formation . This leads to a delay in an early recurrence . ﬁbrinolysis and to deposits on the vascular wall. High The manifestation of a peripheral arterial occlusive dis- concentrations of Lp(a) cause an increased thrombotic risk ease is also inﬂuenced by Lp(a) concentration and a low due to an inhibition of ﬁbrinolytic mechanisms. molecular (NMW) Apo(a) phenotype . The structure of Lp(a) contains about 30% of choles- Finally, numerous published reports on increased Lp(a) terol and cholesterol ester, in addition atherogenous, proim- levels in patients with documented abdominal aortic ﬂammatoray oxidized phospholipids are bonded. This leads aneurysms should be mentioned. This might be an evi- to an accumulation of inﬂammatory cells in the vascular dence for Lp(a)-induced atherosclerotic processes in large wall with consecutive proliferation of smooth muscle cells. vessels . Atherogenesis is thus induced and maintained. Screening Clinical relevance Coronary heart disease Presymptomatic patients with an increased cardiovascular risk are identiﬁed by the determination of classical risk The causative role of Lp(a) in the early manifestation of factors in established scores such as PROCAM, SCORE, coronary heart disease is becoming more and more evident. ASCVD. Earlier studies including meta-analyses have shown that The quality of these scores for risk assessment is not sat- an elevated Lp(a) concentration markedly increases the risk isfying. The sensitivities of these are <50% and the positive for coronary heart disease . In addition, Mendelian ran- predictive value is at most 30% . The establishment of domization has indicated that genetic mutations of Lp(a) new risk factors is therefore of high clinical relevance to in the form of polymorphisms of the Apo(a) kringle IV-2 improve the reliability of prognosis. Considering the ge- repeats are associated with a risk of coronary heart disease netic determination and hereditary burden Lp(a) might be . Patients with a familial hypercholesterolemia (FH) a candidate. of a prospective cohort study, where 46,200 individuals of the Copenhagen General Population Study were enrolled, Therapy showed the highest risk of developing a coronary heart dis- ease in case of Lp(a)≥ 50 mg/dL (HR 5.3, 95% CI 3.6–7.6) . In the GENESIS-PRAXY (GENdEr and Sex determi- So far lipoprotein apheresis is the only effective available nantS of cardiovascular disease) study, 939 young patients therapeutic option to reduce Lp(a) signiﬁcantly, with a doc- admitted for an acute coronary syndrome (ACS) showed an umented effect on cardiac events . association between high Lp(a) (>50 mg/dl) and high LDL- PCSK9 inhibitors reduce LDL cholesterol signiﬁcantly C (>3.5 mmol/L) so that increased Lp(a) and high LDL-C and Lp(a) by about 25–30% . In case of very high ini- represent an increased risk for ACS . tial values of Lp(a), a favourable inﬂuence on athergenous events cannot be expected. A promising approach is the Aortic valve stenosis antisense oligonucleotide therapy. Phase 1 and 2 studies have shown reduction rates of Lp(a) of up to 80% with Aortic valve stenosis may be genetically induced as well a good tolerability . If these results are reproducible as result from a lipid disorder and an Lp(a) increase. in a phase 3 study and cardiovascular events are reduced, A large-scale study has proved that an elevated Lp(a) and a speciﬁc drug therapy of high Lp(a) values might become a corresponding LP risk genotype (rs10455872, rs3798220, available for the ﬁrst time. kringle IV type 2 repeat polymorphism) increase the risk The large number of publications during the past years for the development of aortic valve stenosis . emphasizes the pathophysiological and clinical relevance K Lipoprotein(a) 3 10. 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Clinical Research in Cardiology Supplements – Springer Journals
Published: Apr 3, 2019
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