Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Lipoprotein(a)—an interdisciplinary challenge

Lipoprotein(a)—an interdisciplinary challenge Lipoprotein(a) (Lp(a)) is an internationally recognized atherogenic risk factor which is inherited and not changed by nutrition or physical activity. At present, only proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may modestly decrease its concentration (but not in all patients)—leading to a certain decrease in cardiovascular events (CVE) in controlled studies. However, at present an elevation of Lp(a) is not a generally accepted indication for their use. More effective is lipoprotein apheresis (LA) therapy with respect to both lowering Lp(a) levels and reduction of CVE. In the future, an antisense oligonucleotide against apolipoprotein(a) will probably be available. Atherosclerosis in patients with an elevation of Lp(a) may affect several vessel regions (carotids, aorta, coronaries, leg arteries). Thus, Lp(a) should be measured in high-risk patients. These patients are usually cared for by their family doctors and by other specialists who should closely cooperate. Lipidologists should decide whether costly therapies like PCSK9 inhibitors or LA should be started. The main aim of current therapy is to optimize all other risk factors (LDL cholesterol, hypertension, diabetes mellitus, body weight, renal insufficiency). Patients should be regularly monitored (lab data, heart, arteries). This paper describes the duties of physicians of different specialties when caring for patients with high Lp(a) concentrations. Keywords LDL cholesterol · Cardiovascular events · PCSK9 inhibitors · Physicians · Lipoprotein apheresis Lipoprotein(a)—an internationally accepted Lipoprotein(a)—role in the general risk factor for cardiovascular events population Lipoprotein(a) (Lp(a)) was detected in 1963 [1]. It contains The incidence of elevated Lp(a) concentrations in a given an LDL particle to which apolipoprotein(a) is bound. In the population depends on the criterion which is used. Assum- 1990s studies showed an independent association between ing a rather high cut-off level, elevated Lp(a) levels were elevated Lp(a) levels and the incidence of cardiovascular observed in 10 to 20% of a given population [5, 12, 15]. events [2–4]. Recently, more epidemiological studies have Lp(a) is not influenced by nutritional factors or by physical documented the atherogenic risk of increased Lp(a) con- activity. A hormone deficit in postmenopausal women or centrations [5–11]. This risk has been confirmed by studies renal diseases may increase its concentration. Patients with using a Mendelian randomization and genome-wide asso- a familial hypercholesterolemia often show elevated Lp(a) ciations [6, 12]. Mechanisms leading to atherosclerosis in- levels [16]. clude direct atherogenic, proinflammatory and procoagulant There is no doubt that not all subjects with high Lp(a) activities. However, they are not yet completely understood levels show atherosclerotic lesions. The reasons are still [13]. It is of note that aortic valve stenosis is another pos- quite unclear. The composition of Lp(a) particles may be sible consequence of high Lp(a) concentrations [14]. different. Additional factors most probably play a role: a positive family history with respect to early cardiovas- cular events in first-degree relatives, cigarette smoking, hy- pertension, elevation of low density lipoprotein cholesterol (LDL-C), diabetes mellitus, or a procoagulative situation. This article is part of the special issue “Lp(a) – Update 2018” Thus, a healthy lifestyle and in many patients drug therapy U. Julius are required to avoid or to minimize these additional factors ulrich.julius@uniklinikum-dresden.de in persons with an elevated Lp(a) risk. Routine measurement of Lp(a) levels in a general popu- Lipidology and Center for Extracorporeal Treatment, lation is challenging due to financial reasons. Measurements Department of Internal Medicine III, University Hospital should focus on individuals with high atherogenic risk as Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany listed in Table 1;[17, 18]. K Lipoprotein(a)—an interdisciplinary challenge 21 Table 1 Persons in whom Lp(a) should be measured [17, 18] Lipoprotein(a)—role in the health care system Premature acute coronary syndromes (as well as other atherosclerotic cardiovascular disease (CVD) without apparent cause, e. g. crypto- genic stroke) Medical specialties playing a central role Familial hypercholesterolemia Family history of premature CVD or elevated Lp(a) Fig. 2 summarizes the medical specialties involved in the At least 5–7.5% 10-year risk of CVD (or at intermediate risk based on care for patients with elevated Lp(a) levels. The vast ma- other available risk scores) jority of these patients are seen as outpatients, but severe Individuals with recurrent atherosclerotic cardiovascular events on complications like myocardial infarction, stroke or vascular appropriate secondary prevention therapy interventions require hospitalization. Lp(a) lipoprotein(a) Physicians marked in red in Fig. 2 play a prominent role when attending patients with high Lp(a) levels—their tasks In 2017, Afshar and Thanassoulis [18] also suggested to are described in more detail in the following. measure Lp(a) levels in patients with LDL-C levels above 3.5 mmol/l (135 mg/dl), who would otherwise not qualify Family doctors/general practitioners for statin therapy based on available guidelines. At least in Germany, Lp(a) is recognized as an athero- The family doctor usually knows the family history of his genic risk factor. In 2008 the Joint Federal Committee patients very well and thus can identify high-risk patients (Gemeinsamer Bundesausschuss) accepted an isolated el- whose first-degree relatives suffered from a cardiovascular evation of Lp(a) as an indication for lipoprotein apheresis event at an early age (less than 60 years) or who have (LA) therapy [19] which is a prerequisite for being reim- high Lp(a) levels. He should also consider checking Lp(a) bursed by health insurance companies. levels of other family members who have not yet suffered Fig. 1 depicts the authorities, institutions, societies, or- a cardiovascular event (Fig. 3). ganizations, and persons involved in the management of Many family doctors regularly determine lipid concen- patients who were identified to have an increased cardio- trations of their patients, but some of them do not mea- vascular risk due to elevated Lp(a) concentrations. sure Lp(a)—mainly due to underestimation of the problem As Lp(a) is not yet well-known in the population and “Lp(a)” or for financial restrictions. In high-risk patients, especially among treating physicians, this paper aims to lipids should be checked at least twice per year. give an overview about the current situation concerning the They should advise patients at risk to maintain a healthy diagnostic and therapeutic options. lifestyle (especially no smoking). Usually they pay attention to possible concomitant diseases like hyperlipoproteinemia (elevation of LDL-C or/and triglycerides (TG)), hyperten- sion, diabetes mellitus, slight renal insufficiency. Further- more, regular vascular and cardiological examinations are Fig. 1 Institutions and persons involved in the care for patients with elevated Lp(a). LA lipoprotein apheresis, Lp(a) lipoprotein(a) K 22 U. Julius et al. Fig. 2 Physicians involved in the care for patients with ele- vated Lp(a). Lp(a) lipoprotein(a) Fig. 3 Role of family doctors. Lp(a) lipoprotein(a) important as well as a close cooperation with other spe- After the withdrawal of nicotinic acid from the European cialists who may be contacted in case of complex situa- market, the following therapeutic options to reduce Lp(a) tions, especially when progression of atherosclerosis has levels are available: been documented. 1. PCSK9 inhibitors—decrease Lp(a) by a mean of about 20% (ranging between 0 and 44%); in some patients Lipidologists a reduction cannot be achieved. In two prospective con- trolled large studies, both evolocumab and alirocomab The major aim of referring patients to lipidologists is to induced a modest reduction of cardiovascular events improve the current risk situation with respect to lipoprotein which was the consequence of decreasing Lp(a) lev- concentrations (Fig. 4). The goal is to reach internationally els—independently of the effects on LDL-C [20]. Up to recommended target levels for LDL-C—below 1.8 mmol/l now, an elevation of Lp(a) is no accepted indication for (70 mg/dl) in high-risk patients [17]. Statin therapy is often this injection therapy. modified (increase in dose or switch to another statin when 2. LA—when comparing the Lp(a) levels before initiation an intolerance is reported); sometimes ezetimibe is added. of the extracorporeal therapy with those measured during However, these drugs do not exert a decreasing effect on weekly LA sessions (interval mean values)—a decrease Lp(a) levels. Proprotein convertase subtilisin/kexin type 9 of about 50% is realistic. In two studies, cardiovascular (PCSK9) inhibitors effectively reduce LDL-C levels and events were reduced by about 80% [21–23]. This corre- can be started in therapy-resistant patients (Fig. 4). sponds with the experience of other authors [24–27]. K Lipoprotein(a)—an interdisciplinary challenge 23 Fig. 4 Role of lipidologists. PCSK9 proprotein convertase subtilisin/kexin type 9 In the future, an antisense oligonucleotide against apolipoprotein(a) will probably be available [28, 29]. A phase III study will be started in 2020. However, outcome data are needed before this therapeutic approach will play a major role in daily practice. Cardiologists/Angiologists Some specialists do not measure Lp(a) concentrations; their lab budget is rather restricted. However, an increasing num- ber of them pay attention to this parameter in patients who are at high cardiovascular risk (Table 1) and recommend Fig. 5 Role of cardiologists/angiologists. Lp(a) lipoprotein(a) the family doctor to measure Lp(a) or to send the pa- tient to a lipidological center. According to German regula- The Joint Federal Committee defined three conditions tions, cardiologists/angiologists are authorized to prescribe before an LA therapy can be started: PCSK9 inhibitors. However, this is currently only done in rare cases. a. Lp(a) value ≥60 mg/dl (120 nmol/l), The usual investigations like cardiac ultrasound and er- b. LDL-C in the optimal range (usually below 1.8 mmol/l gometry do not provide an exact follow-up of coronary [70 mg/dl]), atherosclerosis, while cardiac catheterization is only indi- c. A progression of atherosclerosis, either clinically or doc- cated under defined conditions and may lead to adverse umented by imaging techniques [19]. events. Non-invasive techniques like computed tomogra- Lipidologists are required to assess the total atherogenic phy (CT) or magnetic resonance imaging (MRI) will most risk of a given patient before recommending LA treatment. probably play an increasing role in the future. Aortic valve Some lipidologists are allowed to perform LA themselves. stenosis, which can be seen in patients with a high Lp(a) Some health insurance companies require that their medical level, can be easily assessed by echocardiography. services supervise the indication for LA therapy in a few As any vascular region may be affected by atherosclero- cases. sis it is important to examine limb and carotid arteries and The ongoing lipid-modifying drug and LA therapy are the aorta as well (Fig. 5). regarded as satisfactory when no progression of atheroscle- Two important points should still be mentioned: rotic lesions (no new events) occurs. Usually patients are 1. The current findings should always be compared with seen in outpatient departments once every 3 months, in LA previous data—to document or exclude progression of centers weekly. atherosclerosis. K 24 U. Julius et al. Fig. 6 Role of nephrolo- gists. Lp(a) lipoprotein(a), PCSK9 proprotein convertase subtilisin/kexin type 9 2. Patients should be offered a date for the next examina- Diabetologists, endocrinologists, specialists in internal tion—the interval (usually annually or biannually) de- medicine pends on the severity of the arterial lesions. Most patients have to be persuaded to be followed-up. These specialists see patients with hyperlipidemia, metabolic vascular syndrome, hypertension, diabetes mellitus, obesity, Of course, cardiac surgeons and vessel surgeons should and endocrine disorders. In these patients Lp(a) should be send their patients for Lp(a) evaluation following invasive measured. According to the official rules, physicians who procedures. are specialists in both diabetology and endocrinology are allowed to prescribe PCSK9 inhibitors. In complex situa- Nephrologists tions, consultation with a lipidologist is recommended. Renal diseases may increase Lp(a) concentrations. Other Laboratory medicals lipids are also influenced. Nephrologists should regularly measure lipid concentra- It is an accepted opinion that measuring Lp(a) once in a life- tions and should treat disorders, if possible, in cooperation time is sufficient. However, as daily routine has shown that with lipidological and vascular specialists (Fig. 6). Lp(a) levels vary; patients with high levels or those who Nephrologists have the right to prescribe PCSK9 in- undergo Lp(a)-lowering therapy require repeated measure- hibitors and can apply for permission to perform LA ments [30]. therapy. Of course, in apheresis patients attention should also be paid to other risk factors. For application to start Neurologists or to continue LA therapy lipidological and cardiological/ angiological evaluations are required, which confirms the An ischemic stroke may be a consequence of an elevation relevance of the mentioned close cooperation with other of Lp(a), even in children [31, 32]. Neurologists should specialties (Fig. 2). remember this cause, should measure Lp(a) and as a con- sequence should forward these patients to vascular or lipi- Nutritionists dological specialists. Healthy nutrition is the basis for treating patients with lipid Geriatricians disorders. Though Lp(a) is not changed by nutritional fac- tors, LDL-C and TG can be improved. Thus all high-risk In very old patients Lp(a) does not have a prognostic sig- patients with high Lp(a) levels should be advised. nificance—high-risk patients already die at a younger age, although with an increasing quality of medical care, the life expectancy of patients with high Lp(a) levels will probably increase. These patients will need continued medical care K Lipoprotein(a)—an interdisciplinary challenge 25 even beyond the age of 80 years in order to prevent new Activities of the German Lipid Association (Lipid-Liga) cardiovascular events. Gynecologists The German Lipid Association (Lipid-Liga) offers courses to acquire the qualification of a lipidologist. Lp(a) is an Pregnancies affect lipid concentrations. Data on Lp(a) are important topic in these courses. The number of these spe- contradictory; sometimes an elevation was seen [33]. Some cialists is steadily increasing. However, there are regions authors suspected a relationship with pre-eclampsia [34]. where no lipidologist is available yet. It appears to be possible that Lp(a) induces abortions [35, Moreover, the German Lipid Association (Lipid-Liga) 36]. Hormone replacement therapy post-menopause will de- proposes a certification of lipidological outpatient clinics or crease Lp(a) concentrations [37]. lipidological competence centers and networks [39]. Close cooperation with specialists working in the fields mentioned Pediatricians in this paper is an important feature of these structures. This Association also organizes symposia dealing with lipidolog- An elevation of Lp(a) is an inherited disease. In children ical issues, sometimes in cooperation with other societies of parents who suffered from cardiovascular complications (internal medicine, cardiology, angiology, nephrology). associated with high Lp(a) levels this parameter should be measured, in older children an ultrasound examination of the carotids is indicated. When Lp(a) levels are ele- Conclusions vated, follow-up assessments should be performed. Smok- ing should be avoided. In children with familial hyperc- An elevation of Lp(a) concentrations is associated with holesterolemia appropriate therapeutic options should be a high cardiovascular morbidity and mortality. High-risk started (statins, apheresis, etc.) according to the existing patients need special attention. The German government is guidelines. willing to spend money for these purposes and physicians should use the available diagnostic and therapeutic oppor- Psychotherapists tunities. All physicians caring for patients with lipid disorders Patients who suffered from cardiovascular events may need should attend meetings where lipidological topics are pre- the help of a psychotherapist. The risk of new events is sented. Thus a high degree of qualification will be guar- rather high. On the other hand, relatives of affected patients anteed. Close cooperation of different medical specialties may worry about their own future. is needed. Lp(a) really represents an interdisciplinary chal- lenge. Geneticists Conflict of interest U. Julius: honoraria from Aegerion, Akcea, Am- gen, Amryt, Chiesi, Sanofi, Kaneka, Diamed, Fresenius Medical Care, MSD. S. Tselmin: received honoraria for lectures and consulting by The Lp(a) levels are determined by the number of kringles–IV Amgen, Fresenius Medical Care, Kaneka, MSD, and Sanofi-Aventis. type 2 (low numbers are associated with high Lp(a) levels) U. Schatz: No conflicts of interest relevant to this publication. S. Fis- and by certain mutations in the Lp(a) gene. The atherogenic cher: honoraria from Sanofi, Amgen, MSD, Berlin-Chemie, Abbott, risk of Lp(a) is depicted by its level—currently measuring Boehringer Ingelheim. S.R. Bornstein declare that he has no compet- ing interests. the kringles’ number or looking for gene mutations does not play a role in medical practice. However, new findings Open Access This article is distributed under the terms of the in the future may change this attitude. Creative Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give Specialists in intensive medicine appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were Patients with previous myocardial infarction or stroke may made. have been in critical conditions needing intensive care. After recovery Lp(a) measurements in these patients are mandatory, especially in young age [38]. References 1. Berg K (1963) A new serum type system in man—the LP system. Acta Pathol Microbiol Scand 59:369–382 2. Assmann G, Schulte H, von Eckardstein A (1996) Hypertriglyc- eridemia and elevated lipoprotein(a) are risk factors for major coro- nary events in middle-aged men. Am J Cardiol 77(14):1179–1184 K 26 U. Julius et al. 3. Kostner KM, Kostner GM (2017) Lipoprotein (a): a historical 19. Bundesministerium für Gesundheit (2008) Bekanntmachung eines appraisal. J Lipid Res 58(1):1–14. https://doi.org/10.1194/jlr. Beschlusses des Gemeinsamen Bundesausschusses über eine Än- R071571 derung der Richtlinie Methoden vertragsärztliche Versorgung: 4. Cremer P, Nagel D, Mann H, Labrot B, Muller-Berninger R, El- Apherese bei isolierter Lp(a)-Erhöhung. BAnz.138:3321 ster H et al (1997) Ten-year follow-up results from the Goettin- 20. Julius U, Tselmin S, Schatz U, Fischer S, Bornstein SR (2019) gen Risk, Incidence and Prevalence Study (GRIPS). I. Risk factors Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 for myocardial infarction in a cohort of 5790 men. Atherosclerosis (PCSK9) inhibitors. Clin Res Cardiol Suppl. https://doi.org/10. 129(2):221–230 1007/s11789-019-00099-z 5. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts 21. Jaeger BR, Richter Y, Nagel D, Heigl F, Vogt A, Roeseler E et al GF et al (2010) Lipoprotein(a) as a cardiovascular risk factor: cur- (2009) Longitudinal cohort study on the effectiveness of lipid rent status. Eur Heart J 31(23):2844–2853. https://doi.org/10.1093/ apheresis treatment to reduce high lipoprotein(a) levels and prevent eurheartj/ehq386 major adverse coronary events. Nat Clin Pract Cardiovasc Med 6. Tsimikas S (2017) A test in context: lipoprotein(a): diagnosis, prog- 6(3):229–239 nosis, controversies, and emerging therapies. J Am Coll Cardiol 22. Leebmann J, Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling 69(6):692–711. https://doi.org/10.1016/j.jacc.2016.11.042 D et al (2013) Lipoprotein apheresis in patients with maximally tol- 7. Tselmin S, Muller G, Gelgaft E, Fischer S, Julius U (2015) erated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, An elevated lipoprotein(a) plasma level as a cardiovascular risk and progressive cardiovascular disease: prospective observational factor. Atheroscler Suppl 18:257–262. https://doi.org/10.1016/j. multicenter study. Circulation 128(24):2567–2576 atherosclerosissup.2015.02.038 23. Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling D, Breit- 8. Waldeyer C, Makarova N, Zeller T, Schnabel RB, Brunner FJ, Jor- enberger P et al (2016) Lipoprotein apheresis for lipoprotein(a)- gensen T et al (2017) Lipoprotein(a) and the risk of cardiovascu- associated cardiovascular disease: prospective 5 years of follow- lar disease in the European population: results from the Biomar- up and apo(a) characterization. Arterioscler Thromb Vasc Biol CaRE consortium. Eur Heart J 38(32):2490–2498. https://doi.org/ 26:2019–2027. https://doi.org/10.1161/ATVBAHA.116.307983 10.1093/eurheartj/ehx166 24. von Dryander M, Fischer S, Passauer J, Muller G, Bornstein 9. Zewinger S, Kleber ME, Tragante V, McCubrey RO, Schmidt AF, SR, Julius U (2013) Differences in the atherogenic risk of pa- Direk K et al (2017) Relations between lipoprotein(a) concentra- tients treated by lipoprotein apheresis according to their lipid tions, LPA genetic variants, and the risk of mortality in patients with pattern. Atheroscler Suppl 14(1):39–44. https://doi.org/10.1016/j. established coronary heart disease: a molecular and genetic associ- atherosclerosissup.2012.10.005 ation study. Lancet Diabetes Endocrinol 5(7):534–543. https://doi. 25. Emmrich U, Hohenstein B, Julius U (2015) Actual situation org/10.1016/S2213-8587(17)30096-7 of lipoprotein apheresis in Saxony in 2013. Atheroscler Suppl 10. Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Peder- 18:215–225. https://doi.org/10.1016/j.atherosclerosissup.2015.02. sen TR et al (2018) Baseline and on-statin treatment lipopro- 034 tein(a) levels for prediction of cardiovascular events: individ- 26. Schatz U, Tselmin S, Muller G, Julius U, Hohenstein B, Fis- ual patient-data meta-analysis of statin outcome trials. Lancet cher S et al (2017) Most significant reduction of cardiovascular 392(10155):1311–1320. https://doi.org/10.1016/S0140-6736(18) events in patients undergoing lipoproteinapheresis due to raised 31652-0 Lp(a) levels—A multicenter observational study. Atheroscler Suppl 11. Langsted A, Kamstrup PR, Nordestgaard BG (2019) High lipopro- 30:246–252. https://doi.org/10.1016/j.atherosclerosissup.2017.05. tein(a) and high risk of mortality. Eur Heart J. https://doi.org/10. 047 1093/eurheartj/ehy902 27. Julius U (2018) Current role of lipoprotein apheresis in the treat- 12. Kronenberg F (2016) Human genetics and the causal role of ment of high-risk patients. J Cardiovasc Dev Dis. https://doi.org/ lipoprotein(a) for various diseases. Cardiovasc Drugs Ther 30(1): 10.3390/jcdd5020027 87–100. https://doi.org/10.1007/s10557-016-6648-3 28. Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ, 13. Tsimikas S, Fazio S, Ferdinand KC, Ginsberg HN, Koschinsky ML, Baker BF et al (2015) Antisense therapy targeting apolipopro- Marcovina SM et al (2018) NHLBI working group recommenda- tein(a): a randomised, double-blind, placebo-controlled phase tions to reduce lipoprotein(a)-mediated risk of cardiovascular dis- 1 study. Lancet 386(10002):1472–1483. https://doi.org/10.1016/ ease and aortic stenosis. J Am Coll Cardiol 71(2):177–192. https:// S0140-6736(15)61252-1 doi.org/10.1016/j.jacc.2017.11.014 29. Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ 14. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG (2013) Ele- et al (2016) Antisense oligonucleotides targeting apolipoprotein(a) vated lipoprotein(a) and risk of aortic valve stenosis in the general in people with raised lipoprotein(a): two randomised, double- population. J Am Coll Cardiol 63(5):470–477. https://doi.org/10. blind, placebo-controlled, dose-ranging trials. Lancet 388(10057): 1016/j.jacc.2013.09.038 2239–2253. https://doi.org/10.1016/S0140-6736(16)31009-1 15. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG (2011) 30. Marcovina SM, Viney NJ, Hughes SG, Xia S, Witztum JL, Lipoprotein(a) and risk of myocardial infarction—genetic epidemi- Tsimikas S (2018) Temporal variability in lipoprotein(a) levels ologic evidence of causality. Scand J Clin Lab Invest 71(2):87–93. in patients enrolled in the placebo arms of IONIS-APO(a)Rx and https://doi.org/10.3109/00365513.2010.550311 IONIS-APO(a)-LRx antisense oligonucleotide clinical trials. J Clin 16. Li S, Wu NQ, Zhu CG, Zhang Y, Guo YL, Gao Y et al (2017) Sig- Lipidol 12(1):122–129.e2. https://doi.org/10.1016/j.jacl.2017.10. nificance of lipoprotein(a) levels in familial hypercholesterolemia 024 and coronary artery disease. Atherosclerosis 260:67–74. https://doi. 31. Mazhar Z, Hughes A, Garelnabi M (2017) Targeting the role of org/10.1016/j.atherosclerosis.2017.03.021 lipoprotein (a) in stroke. Cardiovasc Hematol Disord Drug Targets 17. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, 17(1):64–72. https://doi.org/10.2174/1871529X176661704211 Drexel H et al (2016) 2016 ESC/EAS Guidelines for the Manage- 50028 ment of Dyslipidaemias. Eur Heart J 37(39):2999–3058. https://doi. 32. Sultan SM, Schupf N, Dowling MM, Deveber GA, Kirton A, org/10.1093/eurheartj/ehw272 Elkind MS (2014) Review of lipid and lipoprotein(a) abnormali- 18. Afshar M, Thanassoulis G (2017) Lipoprotein(a): new insights ties in childhood arterial ischemic stroke. Int J Stroke 9(1):79–87. from modern genomics. Curr Opin Lipidol 28(2):170–176. https:// https://doi.org/10.1111/ijs.12136 doi.org/10.1097/MOL.0000000000000392 K Lipoprotein(a)—an interdisciplinary challenge 27 33. Fanshawe AE, Ibrahim M (2013) The current status of lipopro- 37. Julius U, Fritsch H, Fritsch W, Rehak E, Fucker K, Leonhardt tein (a) in pregnancy: a literature review. J Cardiol 61(2):99–106. W et al (1994) Impact of hormone replacement therapy on post- https://doi.org/10.1016/j.jjcc.2012.09.009 prandial lipoproteins and lipoprotein(a) in normolipidemic post- 34. Parvin S, Samsuddin L, Ali A, Chowdhury SA, Siddique I (2010) menopausal women. Clin Investig 72(7):502–507 Lipoprotein (a) level in pre-eclampsia patients. Bangladesh Med 38. Ellis KL, Pang J, Chieng D, Bell DA, Burnett JR, Schultz CJ et al Res Counc Bull 36(3):97–99 (2018) Elevated lipoprotein(a) and familial hypercholesterolemia in 35. Schettler VJ, Schulz EG, Hagenah GC, Neumann CL (2014) Suc- the coronary care unit: Between Scylla and Charybdis. Clin Cardiol cessful completion of pregnancy using apheresis and a balanced 41(3):378–384. https://doi.org/10.1002/clc.22880 dose of coagulation factors in the presence of high thrombophilia 39. Heigl F, Pflederer T, Schettler V, Grutzmacher P, Julius U, Ringel and Lp(a) levels in a woman with two previous abortions. Clin Kid- J et al (2017) Lipidological competence centres and networks: Fu- ney J 7(5):497–498. https://doi.org/10.1093/ckj/sfu083 ture perspectives to improve healthcare of patients with disorders 36. Romagnuolo I, Sticchi E, Attanasio M, Grifoni E, Cioni G, Cellai of lipid metabolism. Atheroscler Suppl 30:63–71. https://doi.org/ AP et al (2016) Searching for a common mechanism for placenta- 10.1016/j.atherosclerosissup.2017.05.014 mediated pregnancy complications and cardiovascular disease: role of lipoprotein(a). Fertil Steril 105(5):1287–1293.e3. https://doi.org/ 10.1016/j.fertnstert.2016.01.014 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Research in Cardiology Supplements Springer Journals

Lipoprotein(a)—an interdisciplinary challenge

Loading next page...
 
/lp/springer-journals/lipoprotein-a-an-interdisciplinary-challenge-8rnuLA6jfe

References (43)

Publisher
Springer Journals
Copyright
Copyright © 2019 by The Author(s)
Subject
Medicine & Public Health; Cardiology; Internal Medicine; Angiology; Cardiac Surgery; Diagnostic Radiology
ISSN
1861-0706
eISSN
1861-0714
DOI
10.1007/s11789-019-00098-0
Publisher site
See Article on Publisher Site

Abstract

Lipoprotein(a) (Lp(a)) is an internationally recognized atherogenic risk factor which is inherited and not changed by nutrition or physical activity. At present, only proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may modestly decrease its concentration (but not in all patients)—leading to a certain decrease in cardiovascular events (CVE) in controlled studies. However, at present an elevation of Lp(a) is not a generally accepted indication for their use. More effective is lipoprotein apheresis (LA) therapy with respect to both lowering Lp(a) levels and reduction of CVE. In the future, an antisense oligonucleotide against apolipoprotein(a) will probably be available. Atherosclerosis in patients with an elevation of Lp(a) may affect several vessel regions (carotids, aorta, coronaries, leg arteries). Thus, Lp(a) should be measured in high-risk patients. These patients are usually cared for by their family doctors and by other specialists who should closely cooperate. Lipidologists should decide whether costly therapies like PCSK9 inhibitors or LA should be started. The main aim of current therapy is to optimize all other risk factors (LDL cholesterol, hypertension, diabetes mellitus, body weight, renal insufficiency). Patients should be regularly monitored (lab data, heart, arteries). This paper describes the duties of physicians of different specialties when caring for patients with high Lp(a) concentrations. Keywords LDL cholesterol · Cardiovascular events · PCSK9 inhibitors · Physicians · Lipoprotein apheresis Lipoprotein(a)—an internationally accepted Lipoprotein(a)—role in the general risk factor for cardiovascular events population Lipoprotein(a) (Lp(a)) was detected in 1963 [1]. It contains The incidence of elevated Lp(a) concentrations in a given an LDL particle to which apolipoprotein(a) is bound. In the population depends on the criterion which is used. Assum- 1990s studies showed an independent association between ing a rather high cut-off level, elevated Lp(a) levels were elevated Lp(a) levels and the incidence of cardiovascular observed in 10 to 20% of a given population [5, 12, 15]. events [2–4]. Recently, more epidemiological studies have Lp(a) is not influenced by nutritional factors or by physical documented the atherogenic risk of increased Lp(a) con- activity. A hormone deficit in postmenopausal women or centrations [5–11]. This risk has been confirmed by studies renal diseases may increase its concentration. Patients with using a Mendelian randomization and genome-wide asso- a familial hypercholesterolemia often show elevated Lp(a) ciations [6, 12]. Mechanisms leading to atherosclerosis in- levels [16]. clude direct atherogenic, proinflammatory and procoagulant There is no doubt that not all subjects with high Lp(a) activities. However, they are not yet completely understood levels show atherosclerotic lesions. The reasons are still [13]. It is of note that aortic valve stenosis is another pos- quite unclear. The composition of Lp(a) particles may be sible consequence of high Lp(a) concentrations [14]. different. Additional factors most probably play a role: a positive family history with respect to early cardiovas- cular events in first-degree relatives, cigarette smoking, hy- pertension, elevation of low density lipoprotein cholesterol (LDL-C), diabetes mellitus, or a procoagulative situation. This article is part of the special issue “Lp(a) – Update 2018” Thus, a healthy lifestyle and in many patients drug therapy U. Julius are required to avoid or to minimize these additional factors ulrich.julius@uniklinikum-dresden.de in persons with an elevated Lp(a) risk. Routine measurement of Lp(a) levels in a general popu- Lipidology and Center for Extracorporeal Treatment, lation is challenging due to financial reasons. Measurements Department of Internal Medicine III, University Hospital should focus on individuals with high atherogenic risk as Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany listed in Table 1;[17, 18]. K Lipoprotein(a)—an interdisciplinary challenge 21 Table 1 Persons in whom Lp(a) should be measured [17, 18] Lipoprotein(a)—role in the health care system Premature acute coronary syndromes (as well as other atherosclerotic cardiovascular disease (CVD) without apparent cause, e. g. crypto- genic stroke) Medical specialties playing a central role Familial hypercholesterolemia Family history of premature CVD or elevated Lp(a) Fig. 2 summarizes the medical specialties involved in the At least 5–7.5% 10-year risk of CVD (or at intermediate risk based on care for patients with elevated Lp(a) levels. The vast ma- other available risk scores) jority of these patients are seen as outpatients, but severe Individuals with recurrent atherosclerotic cardiovascular events on complications like myocardial infarction, stroke or vascular appropriate secondary prevention therapy interventions require hospitalization. Lp(a) lipoprotein(a) Physicians marked in red in Fig. 2 play a prominent role when attending patients with high Lp(a) levels—their tasks In 2017, Afshar and Thanassoulis [18] also suggested to are described in more detail in the following. measure Lp(a) levels in patients with LDL-C levels above 3.5 mmol/l (135 mg/dl), who would otherwise not qualify Family doctors/general practitioners for statin therapy based on available guidelines. At least in Germany, Lp(a) is recognized as an athero- The family doctor usually knows the family history of his genic risk factor. In 2008 the Joint Federal Committee patients very well and thus can identify high-risk patients (Gemeinsamer Bundesausschuss) accepted an isolated el- whose first-degree relatives suffered from a cardiovascular evation of Lp(a) as an indication for lipoprotein apheresis event at an early age (less than 60 years) or who have (LA) therapy [19] which is a prerequisite for being reim- high Lp(a) levels. He should also consider checking Lp(a) bursed by health insurance companies. levels of other family members who have not yet suffered Fig. 1 depicts the authorities, institutions, societies, or- a cardiovascular event (Fig. 3). ganizations, and persons involved in the management of Many family doctors regularly determine lipid concen- patients who were identified to have an increased cardio- trations of their patients, but some of them do not mea- vascular risk due to elevated Lp(a) concentrations. sure Lp(a)—mainly due to underestimation of the problem As Lp(a) is not yet well-known in the population and “Lp(a)” or for financial restrictions. In high-risk patients, especially among treating physicians, this paper aims to lipids should be checked at least twice per year. give an overview about the current situation concerning the They should advise patients at risk to maintain a healthy diagnostic and therapeutic options. lifestyle (especially no smoking). Usually they pay attention to possible concomitant diseases like hyperlipoproteinemia (elevation of LDL-C or/and triglycerides (TG)), hyperten- sion, diabetes mellitus, slight renal insufficiency. Further- more, regular vascular and cardiological examinations are Fig. 1 Institutions and persons involved in the care for patients with elevated Lp(a). LA lipoprotein apheresis, Lp(a) lipoprotein(a) K 22 U. Julius et al. Fig. 2 Physicians involved in the care for patients with ele- vated Lp(a). Lp(a) lipoprotein(a) Fig. 3 Role of family doctors. Lp(a) lipoprotein(a) important as well as a close cooperation with other spe- After the withdrawal of nicotinic acid from the European cialists who may be contacted in case of complex situa- market, the following therapeutic options to reduce Lp(a) tions, especially when progression of atherosclerosis has levels are available: been documented. 1. PCSK9 inhibitors—decrease Lp(a) by a mean of about 20% (ranging between 0 and 44%); in some patients Lipidologists a reduction cannot be achieved. In two prospective con- trolled large studies, both evolocumab and alirocomab The major aim of referring patients to lipidologists is to induced a modest reduction of cardiovascular events improve the current risk situation with respect to lipoprotein which was the consequence of decreasing Lp(a) lev- concentrations (Fig. 4). The goal is to reach internationally els—independently of the effects on LDL-C [20]. Up to recommended target levels for LDL-C—below 1.8 mmol/l now, an elevation of Lp(a) is no accepted indication for (70 mg/dl) in high-risk patients [17]. Statin therapy is often this injection therapy. modified (increase in dose or switch to another statin when 2. LA—when comparing the Lp(a) levels before initiation an intolerance is reported); sometimes ezetimibe is added. of the extracorporeal therapy with those measured during However, these drugs do not exert a decreasing effect on weekly LA sessions (interval mean values)—a decrease Lp(a) levels. Proprotein convertase subtilisin/kexin type 9 of about 50% is realistic. In two studies, cardiovascular (PCSK9) inhibitors effectively reduce LDL-C levels and events were reduced by about 80% [21–23]. This corre- can be started in therapy-resistant patients (Fig. 4). sponds with the experience of other authors [24–27]. K Lipoprotein(a)—an interdisciplinary challenge 23 Fig. 4 Role of lipidologists. PCSK9 proprotein convertase subtilisin/kexin type 9 In the future, an antisense oligonucleotide against apolipoprotein(a) will probably be available [28, 29]. A phase III study will be started in 2020. However, outcome data are needed before this therapeutic approach will play a major role in daily practice. Cardiologists/Angiologists Some specialists do not measure Lp(a) concentrations; their lab budget is rather restricted. However, an increasing num- ber of them pay attention to this parameter in patients who are at high cardiovascular risk (Table 1) and recommend Fig. 5 Role of cardiologists/angiologists. Lp(a) lipoprotein(a) the family doctor to measure Lp(a) or to send the pa- tient to a lipidological center. According to German regula- The Joint Federal Committee defined three conditions tions, cardiologists/angiologists are authorized to prescribe before an LA therapy can be started: PCSK9 inhibitors. However, this is currently only done in rare cases. a. Lp(a) value ≥60 mg/dl (120 nmol/l), The usual investigations like cardiac ultrasound and er- b. LDL-C in the optimal range (usually below 1.8 mmol/l gometry do not provide an exact follow-up of coronary [70 mg/dl]), atherosclerosis, while cardiac catheterization is only indi- c. A progression of atherosclerosis, either clinically or doc- cated under defined conditions and may lead to adverse umented by imaging techniques [19]. events. Non-invasive techniques like computed tomogra- Lipidologists are required to assess the total atherogenic phy (CT) or magnetic resonance imaging (MRI) will most risk of a given patient before recommending LA treatment. probably play an increasing role in the future. Aortic valve Some lipidologists are allowed to perform LA themselves. stenosis, which can be seen in patients with a high Lp(a) Some health insurance companies require that their medical level, can be easily assessed by echocardiography. services supervise the indication for LA therapy in a few As any vascular region may be affected by atherosclero- cases. sis it is important to examine limb and carotid arteries and The ongoing lipid-modifying drug and LA therapy are the aorta as well (Fig. 5). regarded as satisfactory when no progression of atheroscle- Two important points should still be mentioned: rotic lesions (no new events) occurs. Usually patients are 1. The current findings should always be compared with seen in outpatient departments once every 3 months, in LA previous data—to document or exclude progression of centers weekly. atherosclerosis. K 24 U. Julius et al. Fig. 6 Role of nephrolo- gists. Lp(a) lipoprotein(a), PCSK9 proprotein convertase subtilisin/kexin type 9 2. Patients should be offered a date for the next examina- Diabetologists, endocrinologists, specialists in internal tion—the interval (usually annually or biannually) de- medicine pends on the severity of the arterial lesions. Most patients have to be persuaded to be followed-up. These specialists see patients with hyperlipidemia, metabolic vascular syndrome, hypertension, diabetes mellitus, obesity, Of course, cardiac surgeons and vessel surgeons should and endocrine disorders. In these patients Lp(a) should be send their patients for Lp(a) evaluation following invasive measured. According to the official rules, physicians who procedures. are specialists in both diabetology and endocrinology are allowed to prescribe PCSK9 inhibitors. In complex situa- Nephrologists tions, consultation with a lipidologist is recommended. Renal diseases may increase Lp(a) concentrations. Other Laboratory medicals lipids are also influenced. Nephrologists should regularly measure lipid concentra- It is an accepted opinion that measuring Lp(a) once in a life- tions and should treat disorders, if possible, in cooperation time is sufficient. However, as daily routine has shown that with lipidological and vascular specialists (Fig. 6). Lp(a) levels vary; patients with high levels or those who Nephrologists have the right to prescribe PCSK9 in- undergo Lp(a)-lowering therapy require repeated measure- hibitors and can apply for permission to perform LA ments [30]. therapy. Of course, in apheresis patients attention should also be paid to other risk factors. For application to start Neurologists or to continue LA therapy lipidological and cardiological/ angiological evaluations are required, which confirms the An ischemic stroke may be a consequence of an elevation relevance of the mentioned close cooperation with other of Lp(a), even in children [31, 32]. Neurologists should specialties (Fig. 2). remember this cause, should measure Lp(a) and as a con- sequence should forward these patients to vascular or lipi- Nutritionists dological specialists. Healthy nutrition is the basis for treating patients with lipid Geriatricians disorders. Though Lp(a) is not changed by nutritional fac- tors, LDL-C and TG can be improved. Thus all high-risk In very old patients Lp(a) does not have a prognostic sig- patients with high Lp(a) levels should be advised. nificance—high-risk patients already die at a younger age, although with an increasing quality of medical care, the life expectancy of patients with high Lp(a) levels will probably increase. These patients will need continued medical care K Lipoprotein(a)—an interdisciplinary challenge 25 even beyond the age of 80 years in order to prevent new Activities of the German Lipid Association (Lipid-Liga) cardiovascular events. Gynecologists The German Lipid Association (Lipid-Liga) offers courses to acquire the qualification of a lipidologist. Lp(a) is an Pregnancies affect lipid concentrations. Data on Lp(a) are important topic in these courses. The number of these spe- contradictory; sometimes an elevation was seen [33]. Some cialists is steadily increasing. However, there are regions authors suspected a relationship with pre-eclampsia [34]. where no lipidologist is available yet. It appears to be possible that Lp(a) induces abortions [35, Moreover, the German Lipid Association (Lipid-Liga) 36]. Hormone replacement therapy post-menopause will de- proposes a certification of lipidological outpatient clinics or crease Lp(a) concentrations [37]. lipidological competence centers and networks [39]. Close cooperation with specialists working in the fields mentioned Pediatricians in this paper is an important feature of these structures. This Association also organizes symposia dealing with lipidolog- An elevation of Lp(a) is an inherited disease. In children ical issues, sometimes in cooperation with other societies of parents who suffered from cardiovascular complications (internal medicine, cardiology, angiology, nephrology). associated with high Lp(a) levels this parameter should be measured, in older children an ultrasound examination of the carotids is indicated. When Lp(a) levels are ele- Conclusions vated, follow-up assessments should be performed. Smok- ing should be avoided. In children with familial hyperc- An elevation of Lp(a) concentrations is associated with holesterolemia appropriate therapeutic options should be a high cardiovascular morbidity and mortality. High-risk started (statins, apheresis, etc.) according to the existing patients need special attention. The German government is guidelines. willing to spend money for these purposes and physicians should use the available diagnostic and therapeutic oppor- Psychotherapists tunities. All physicians caring for patients with lipid disorders Patients who suffered from cardiovascular events may need should attend meetings where lipidological topics are pre- the help of a psychotherapist. The risk of new events is sented. Thus a high degree of qualification will be guar- rather high. On the other hand, relatives of affected patients anteed. Close cooperation of different medical specialties may worry about their own future. is needed. Lp(a) really represents an interdisciplinary chal- lenge. Geneticists Conflict of interest U. Julius: honoraria from Aegerion, Akcea, Am- gen, Amryt, Chiesi, Sanofi, Kaneka, Diamed, Fresenius Medical Care, MSD. S. Tselmin: received honoraria for lectures and consulting by The Lp(a) levels are determined by the number of kringles–IV Amgen, Fresenius Medical Care, Kaneka, MSD, and Sanofi-Aventis. type 2 (low numbers are associated with high Lp(a) levels) U. Schatz: No conflicts of interest relevant to this publication. S. Fis- and by certain mutations in the Lp(a) gene. The atherogenic cher: honoraria from Sanofi, Amgen, MSD, Berlin-Chemie, Abbott, risk of Lp(a) is depicted by its level—currently measuring Boehringer Ingelheim. S.R. Bornstein declare that he has no compet- ing interests. the kringles’ number or looking for gene mutations does not play a role in medical practice. However, new findings Open Access This article is distributed under the terms of the in the future may change this attitude. Creative Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give Specialists in intensive medicine appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were Patients with previous myocardial infarction or stroke may made. have been in critical conditions needing intensive care. After recovery Lp(a) measurements in these patients are mandatory, especially in young age [38]. References 1. Berg K (1963) A new serum type system in man—the LP system. Acta Pathol Microbiol Scand 59:369–382 2. Assmann G, Schulte H, von Eckardstein A (1996) Hypertriglyc- eridemia and elevated lipoprotein(a) are risk factors for major coro- nary events in middle-aged men. Am J Cardiol 77(14):1179–1184 K 26 U. Julius et al. 3. Kostner KM, Kostner GM (2017) Lipoprotein (a): a historical 19. Bundesministerium für Gesundheit (2008) Bekanntmachung eines appraisal. J Lipid Res 58(1):1–14. https://doi.org/10.1194/jlr. Beschlusses des Gemeinsamen Bundesausschusses über eine Än- R071571 derung der Richtlinie Methoden vertragsärztliche Versorgung: 4. Cremer P, Nagel D, Mann H, Labrot B, Muller-Berninger R, El- Apherese bei isolierter Lp(a)-Erhöhung. BAnz.138:3321 ster H et al (1997) Ten-year follow-up results from the Goettin- 20. Julius U, Tselmin S, Schatz U, Fischer S, Bornstein SR (2019) gen Risk, Incidence and Prevalence Study (GRIPS). I. Risk factors Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 for myocardial infarction in a cohort of 5790 men. Atherosclerosis (PCSK9) inhibitors. Clin Res Cardiol Suppl. https://doi.org/10. 129(2):221–230 1007/s11789-019-00099-z 5. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts 21. Jaeger BR, Richter Y, Nagel D, Heigl F, Vogt A, Roeseler E et al GF et al (2010) Lipoprotein(a) as a cardiovascular risk factor: cur- (2009) Longitudinal cohort study on the effectiveness of lipid rent status. Eur Heart J 31(23):2844–2853. https://doi.org/10.1093/ apheresis treatment to reduce high lipoprotein(a) levels and prevent eurheartj/ehq386 major adverse coronary events. Nat Clin Pract Cardiovasc Med 6. Tsimikas S (2017) A test in context: lipoprotein(a): diagnosis, prog- 6(3):229–239 nosis, controversies, and emerging therapies. J Am Coll Cardiol 22. Leebmann J, Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling 69(6):692–711. https://doi.org/10.1016/j.jacc.2016.11.042 D et al (2013) Lipoprotein apheresis in patients with maximally tol- 7. Tselmin S, Muller G, Gelgaft E, Fischer S, Julius U (2015) erated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, An elevated lipoprotein(a) plasma level as a cardiovascular risk and progressive cardiovascular disease: prospective observational factor. Atheroscler Suppl 18:257–262. https://doi.org/10.1016/j. multicenter study. Circulation 128(24):2567–2576 atherosclerosissup.2015.02.038 23. Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling D, Breit- 8. Waldeyer C, Makarova N, Zeller T, Schnabel RB, Brunner FJ, Jor- enberger P et al (2016) Lipoprotein apheresis for lipoprotein(a)- gensen T et al (2017) Lipoprotein(a) and the risk of cardiovascu- associated cardiovascular disease: prospective 5 years of follow- lar disease in the European population: results from the Biomar- up and apo(a) characterization. Arterioscler Thromb Vasc Biol CaRE consortium. Eur Heart J 38(32):2490–2498. https://doi.org/ 26:2019–2027. https://doi.org/10.1161/ATVBAHA.116.307983 10.1093/eurheartj/ehx166 24. von Dryander M, Fischer S, Passauer J, Muller G, Bornstein 9. Zewinger S, Kleber ME, Tragante V, McCubrey RO, Schmidt AF, SR, Julius U (2013) Differences in the atherogenic risk of pa- Direk K et al (2017) Relations between lipoprotein(a) concentra- tients treated by lipoprotein apheresis according to their lipid tions, LPA genetic variants, and the risk of mortality in patients with pattern. Atheroscler Suppl 14(1):39–44. https://doi.org/10.1016/j. established coronary heart disease: a molecular and genetic associ- atherosclerosissup.2012.10.005 ation study. Lancet Diabetes Endocrinol 5(7):534–543. https://doi. 25. Emmrich U, Hohenstein B, Julius U (2015) Actual situation org/10.1016/S2213-8587(17)30096-7 of lipoprotein apheresis in Saxony in 2013. Atheroscler Suppl 10. Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Peder- 18:215–225. https://doi.org/10.1016/j.atherosclerosissup.2015.02. sen TR et al (2018) Baseline and on-statin treatment lipopro- 034 tein(a) levels for prediction of cardiovascular events: individ- 26. Schatz U, Tselmin S, Muller G, Julius U, Hohenstein B, Fis- ual patient-data meta-analysis of statin outcome trials. Lancet cher S et al (2017) Most significant reduction of cardiovascular 392(10155):1311–1320. https://doi.org/10.1016/S0140-6736(18) events in patients undergoing lipoproteinapheresis due to raised 31652-0 Lp(a) levels—A multicenter observational study. Atheroscler Suppl 11. Langsted A, Kamstrup PR, Nordestgaard BG (2019) High lipopro- 30:246–252. https://doi.org/10.1016/j.atherosclerosissup.2017.05. tein(a) and high risk of mortality. Eur Heart J. https://doi.org/10. 047 1093/eurheartj/ehy902 27. Julius U (2018) Current role of lipoprotein apheresis in the treat- 12. Kronenberg F (2016) Human genetics and the causal role of ment of high-risk patients. J Cardiovasc Dev Dis. https://doi.org/ lipoprotein(a) for various diseases. Cardiovasc Drugs Ther 30(1): 10.3390/jcdd5020027 87–100. https://doi.org/10.1007/s10557-016-6648-3 28. Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ, 13. Tsimikas S, Fazio S, Ferdinand KC, Ginsberg HN, Koschinsky ML, Baker BF et al (2015) Antisense therapy targeting apolipopro- Marcovina SM et al (2018) NHLBI working group recommenda- tein(a): a randomised, double-blind, placebo-controlled phase tions to reduce lipoprotein(a)-mediated risk of cardiovascular dis- 1 study. Lancet 386(10002):1472–1483. https://doi.org/10.1016/ ease and aortic stenosis. J Am Coll Cardiol 71(2):177–192. https:// S0140-6736(15)61252-1 doi.org/10.1016/j.jacc.2017.11.014 29. Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ 14. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG (2013) Ele- et al (2016) Antisense oligonucleotides targeting apolipoprotein(a) vated lipoprotein(a) and risk of aortic valve stenosis in the general in people with raised lipoprotein(a): two randomised, double- population. J Am Coll Cardiol 63(5):470–477. https://doi.org/10. blind, placebo-controlled, dose-ranging trials. Lancet 388(10057): 1016/j.jacc.2013.09.038 2239–2253. https://doi.org/10.1016/S0140-6736(16)31009-1 15. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG (2011) 30. Marcovina SM, Viney NJ, Hughes SG, Xia S, Witztum JL, Lipoprotein(a) and risk of myocardial infarction—genetic epidemi- Tsimikas S (2018) Temporal variability in lipoprotein(a) levels ologic evidence of causality. Scand J Clin Lab Invest 71(2):87–93. in patients enrolled in the placebo arms of IONIS-APO(a)Rx and https://doi.org/10.3109/00365513.2010.550311 IONIS-APO(a)-LRx antisense oligonucleotide clinical trials. J Clin 16. Li S, Wu NQ, Zhu CG, Zhang Y, Guo YL, Gao Y et al (2017) Sig- Lipidol 12(1):122–129.e2. https://doi.org/10.1016/j.jacl.2017.10. nificance of lipoprotein(a) levels in familial hypercholesterolemia 024 and coronary artery disease. Atherosclerosis 260:67–74. https://doi. 31. Mazhar Z, Hughes A, Garelnabi M (2017) Targeting the role of org/10.1016/j.atherosclerosis.2017.03.021 lipoprotein (a) in stroke. Cardiovasc Hematol Disord Drug Targets 17. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, 17(1):64–72. https://doi.org/10.2174/1871529X176661704211 Drexel H et al (2016) 2016 ESC/EAS Guidelines for the Manage- 50028 ment of Dyslipidaemias. Eur Heart J 37(39):2999–3058. https://doi. 32. Sultan SM, Schupf N, Dowling MM, Deveber GA, Kirton A, org/10.1093/eurheartj/ehw272 Elkind MS (2014) Review of lipid and lipoprotein(a) abnormali- 18. Afshar M, Thanassoulis G (2017) Lipoprotein(a): new insights ties in childhood arterial ischemic stroke. Int J Stroke 9(1):79–87. from modern genomics. Curr Opin Lipidol 28(2):170–176. https:// https://doi.org/10.1111/ijs.12136 doi.org/10.1097/MOL.0000000000000392 K Lipoprotein(a)—an interdisciplinary challenge 27 33. Fanshawe AE, Ibrahim M (2013) The current status of lipopro- 37. Julius U, Fritsch H, Fritsch W, Rehak E, Fucker K, Leonhardt tein (a) in pregnancy: a literature review. J Cardiol 61(2):99–106. W et al (1994) Impact of hormone replacement therapy on post- https://doi.org/10.1016/j.jjcc.2012.09.009 prandial lipoproteins and lipoprotein(a) in normolipidemic post- 34. Parvin S, Samsuddin L, Ali A, Chowdhury SA, Siddique I (2010) menopausal women. Clin Investig 72(7):502–507 Lipoprotein (a) level in pre-eclampsia patients. Bangladesh Med 38. Ellis KL, Pang J, Chieng D, Bell DA, Burnett JR, Schultz CJ et al Res Counc Bull 36(3):97–99 (2018) Elevated lipoprotein(a) and familial hypercholesterolemia in 35. Schettler VJ, Schulz EG, Hagenah GC, Neumann CL (2014) Suc- the coronary care unit: Between Scylla and Charybdis. Clin Cardiol cessful completion of pregnancy using apheresis and a balanced 41(3):378–384. https://doi.org/10.1002/clc.22880 dose of coagulation factors in the presence of high thrombophilia 39. Heigl F, Pflederer T, Schettler V, Grutzmacher P, Julius U, Ringel and Lp(a) levels in a woman with two previous abortions. Clin Kid- J et al (2017) Lipidological competence centres and networks: Fu- ney J 7(5):497–498. https://doi.org/10.1093/ckj/sfu083 ture perspectives to improve healthcare of patients with disorders 36. Romagnuolo I, Sticchi E, Attanasio M, Grifoni E, Cioni G, Cellai of lipid metabolism. Atheroscler Suppl 30:63–71. https://doi.org/ AP et al (2016) Searching for a common mechanism for placenta- 10.1016/j.atherosclerosissup.2017.05.014 mediated pregnancy complications and cardiovascular disease: role of lipoprotein(a). Fertil Steril 105(5):1287–1293.e3. https://doi.org/ 10.1016/j.fertnstert.2016.01.014

Journal

Clinical Research in Cardiology SupplementsSpringer Journals

Published: Mar 5, 2019

There are no references for this article.