Genetic testing of familial hypercholesterolemia in clinical practice: statement of Czech Society for Atherosclerosis


Authors: Michal Vrablík 1;  Vladimír Bláha 2;  Renata Cífková 3;  Tomáš Freiberger 4;  David Karásek 5;  Pavel Kraml 6;  Jan Piťha 7;  Hana Rosolová 8;  Vladimír Soška 9;  Tomáš Štulc 1;  Lukáš Tichý 10;  Zuzana Urbanová Za Výbor Čsat 11;  Jana Mašková 12
Authors‘ workplace: III. interní klinika - endokrinologie a metabolismu 1. LF UK a VFN v Praze 1;  Interní hematoonkologická klinika, Centrum molekulární biologie a genové terapie FN Brno 10;  Klinika dětského a dorostového lékařství 1. LF UK a VFN v Praze 11;  NEOX Clinical Research, Praha 12;  III. interní gerontometabolická klinika LF UK a FN Hradec Králové 2;  Centrum kardiovaskulární prevence 1. LF UK a Thomayerova nemocnice, Praha 3;  Centrum kardiovaskulární a transplantační chirurgie, Brno 4;  III. interní klinika – nefrologická, revmatologická a endokrinologická LF UP a FN Olomouc 5;  II. interní klinika 3. LF a FN Královské Vinohrady, Praha 6;  Interní klinika 2. LF UK a FN Motol a Laboratoř pro výzkum aterosklerózy IKEM, Praha 7;  II. interní klinika LF UK a FN Plzeň 8;  Oddělení klinické biochemie, II. interní klinika LF MU a FN u sv. Anny v Brně 9
Published in: AtheroRev 2020; 5(3): 147-157
Category: Guidelines

Overview

Although awareness about familial hypercholesterolemia (FH) is increasing, this widespread and potentially fatal, but treatable disease, remains underdiagnosed. Although FH is an inherited condition, genetic testing for this disease is still rare. The Familial Hypercholesterolemia Foundation convened an international panel of experts to evaluate the usefulness of molecular genetic testing for FH. The findings that form the basis for justification of the examination are as follows: (1) detection of a causal mutation facilitates the definitive diagnosis (2) presence of a pathogenic mutation involves a higher cardiovascular risk and potentially requires more aggressive lipid lowering (3) for genetically demonstrated FH, there is an increased likeli­hood of early initiation of and adherence to treatment; and (4) the knowledge of the causal mutation essentially facilitates the cascade examination of relatives at risk. The consensus of the panel of experts recommends that genetic testing for FH becomes a standard in the care of patients with verified or likely FH and their relatives at risk. The genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (apoB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) should be tested. Other genes can be included in the examination according to the patient’s phenotype. The benefits will be an increase in the number of diagnosed patients, a more effective cascade examination, initiation of treatment at an earlier age and more accurate risk identification.

Keywords:

cardiovascular risk – APOB gen – Familial Hypercholesterolemia Foundation – genetic testing – LDLR gen – PCSK9 gen – familiární hypercholesterolemie


Sources

Seznam citované literatury je číslován podle originálního anglického textu [1]. Položky [4–6], [11], [14], [33], [37,38], [42,43], [45–48], [51–72], [74,75], [79–81], [94–100], [106,108,109], [118–126] ve výše uvedeném textu stanoviska citovány nejsou. Úplný seznam citované literatury je dostupný z DOI: <http://dx.doi.org/10.1016/j.jacc.2018.05.044>.

1.   Sturm AC, Knowles JW, Gidding SS et al. [Convened by the Familial Hypercholesterolemia Foundation]. Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel J Am Coll Cardiol 2018; 72(6): 662–680. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacc.2018.05.044>.

2.   Watts GF, Sullivan DR, Poplawski N et al. Familial hypercholesterolaemia: a model of care for Australasia. Atherosclerosis 2011; 12(2): 221–263. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosissup.2011.06.001>.

3.   Watts GF, Gidding S, Wierzbicki AS et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int J Cardiol 2014; 171(3): 309–325. Dostupné z DOI: <http://dx.doi.org/10.1016/j.ijcard.2013.11.025>.

7.   Abul-Husn NS, Manickam K, Jones LK et al. Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science 2016; 354(6319): aaf7000. Dostupné z DOI: <http://dx.doi.org/10.1126/science.aaf7000>.

8.   Benn M, Watts G, Tybjærg-Hansen A et al. Corrigendum to “Familial Hypercholesterolemia in the Danish General Population: Prevalence, Coronary Artery Disease, and Cholesterol-Lowering Medication”. J Clin Endocrinol Metab 2014; 99(11): 4758–4759. Dostupné z DOI: <https://doi.org/10.1210/jc.2014–3926>.

9.   Benn M, Watts GF, Tybjaerg-Hansen A et al. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab 2012; 97(11): 3956–3964. Dostupné z DOI: <https://doi.org/10.1210/jc.2012–1563>.

10.  Wald DS, Bestwick JP, Morris JK et al. Child-parent familial hypercholesterolemia screening in primary care. N Engl J Med 2016; 375(17): 1628–1637. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1602777>.

12.  Slack J. Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet 1969; 2(7635): 1380–1382. Dostupné z DOI: <http://dx.doi.org/10.1016/s0140–6736(69)90930–1>.

13.  Stone NJ, Levy RI, Fredrickson DS et al. Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia. Circulation 1974; 49(3): 476–488. Dostupné z DOI: <http://dx.doi.org/10.1161/01.cir.49.3.476>.

15.  Versmissen J, Oosterveer DM, Yazdanpanah M et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 2008; 337: a2423. Dostupné z DOI: <http://dx.doi.org/10.1136/bmj.a2423>.

16.  Braamskamp MJ, Kastelein JJ, Kusters DM et al. Statin initiation during childhood in patients with familial hypercholesterolemia: consequences for cardiovascular risk. J Am Coll Cardiol 2016; 67(4): 455–456. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacc.2015.11.021>.

17.  Neil A, Cooper J, Betteridge J et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J 2008; 29(21):2625–2633. Dostupné z DOI: <http://dx.doi.org/10.1093/eurheartj/ehn422>.

18.  Gidding SS, Champagne MA, de Ferranti SD et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation 2015; 132(22): 2167–2192. Dostupné z DOI: <http://dx.doi.org/10.1161/CIR.0000000000000297>.

19.  Cuchel M, Bruckert E, Ginsberg HN et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014; 35(32): 2146–2157. Dostupné z DOI: <http://dx.doi.org/10.1093/eurheartj/ehu274>.

20.  Sjouke B, Hovingh GK, Kastelein JJ et al. Homozygous autosomal dominant hypercholesterolaemia: prevalence, diagnosis, and current and future treatment perspectives. Curr Opin Lipidol 2015; 26(3):200–209. Dostupné z DOI: <http://dx.doi.org/10.1097/MOL.0000000000000179>.

21.  Futema M, Shah S, Cooper JA et al. Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries. Clin Chem 2015; 61(1): 231–238. Dostupné z DOI: <http://dx.doi.org/10.1373/clinchem.2014.231365>.

22.  Talmud PJ, Shah S, Whittall R et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet 2013; 381(9874): 1293–1301. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(12)62127–8>.

23.  Braenne I, Kleinecke M, Reiz B. et al. Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. Eur J Hum Genet 2016; 24(2): 191–197. Dostupné z DOI: <http://dx.doi.org/10.1038/ejhg.2015.100>.

24.  Nordestgaard BG, Benn M. Genetic testing for familial hypercholesterolaemia is essential in individuals with high LDL cholesterol: who does it in the world? Eur Heart J 2017; 38(20): 1580–1583. Dostupné z DOI: <http://dx.doi.org/10.1093/eurheartj/ehx136>.

25.  Nordestgaard BG, Chapman MJ, Humphries SE et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013; 34(45): 3478–3490a. Dostupné z DOI: <http://dx.doi.org/10.1093/eurheartj/eht273>.

26.  Knickelbine T, Lui M, Garberich R et al. Familial hypercholesterolemia in a large ambulatory population: statin use, optimal treatment, and identification for advanced medical therapies. J Clin Lipidol 2016; 10(5): 1182–1187. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacl.2016.05.007>.

27.  Ahmad ZS, Andersen RL, Andersen LH et al. US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry. J Clin Lipidol 2016; 10(5): 1223–1229. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacl.2016.07.011>.

28.  Vrablik M, Vaclova M, Tichy L et al. Familial hypercholesterolemia in the Czech Republic: more than 17 years of systematic screening within the MedPed project. Physiol Res 2017; 66(Suppl 1): S1–S9. Dostupné z DOI: <http://dx.doi.org/10.33549/physiolres.933600>.

29.  Defesche JC, Lansberg PJ, Umans-Eckenhausen MA et al. Advanced method for the identification of patients with inherited hypercholesterolemia. Semin Vasc Med 2004; 4(1): 59–65. Dostupné z DOI: <http://dx.doi.org/10.1055/s-2004–822987>.

30.  Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ 1991; 303(6807): 893–896. Dostupné z DOI: <http://dx.doi.org/10.1136/bmj.303.6807.893>.

31.  Humphries SE, Norbury G, Leigh S et al. What is the clinical utility of DNA testing in patients with familial hypercholesterolaemia? Curr Opin Lipidol 2008; 19(4):362–368. Dostupné z DOI: <http://dx.doi.org/10.1097/MOL.0b013e32830636e5>.

32.  Kindt I, Mata P, Knowles JW. The role of registries and genetic databases in familial hypercholesterolemia. Curr Opin Lipidol 2017; 28(2):152–160. Dostupné z DOI: <http://dx.doi.org/10.1097/MOL.0000000000000398>.

34.  Perez de Isla L, Alonso R, Watts GF et al. Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up. J Am Coll Cardiol 2016; 67(11): 1278–1285. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacc.2016.01.008>.

35.  Leren TP. Cascade genetic screening for familial hypercholesterolemia. Clin Genet 2004; 66(6): 483–487. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1399–0004.2004.00320.x>.

36.  Khera AV, Won HH, Peloso GM et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol 2016; 67(22): 2578–2589. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacc.2016.03.520>.

39.  Klancar G, Groselj U, Kovac J et al. Universal screening for familial hypercholesterolemia in children. J Am Coll Cardiol 2015; 66(11): 1250–1257. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacc.2015.07.017>.

40.  Wiegman A, Gidding SS, Watts GF et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015; 36(36): 2425–2437. Dostupné z DOI: <http://dx.doi.org/10.1093/eurheartj/ehv157>.

41.  Huijgen R., Hutten B.A., Kindt I et al. Discriminative ability of LDL-cholesterol to identify patients with familial hypercholesterolemia: a cross-sectional study in 26,406 individuals tested for genetic FH. Circ Cardiovasc Genet 2012; 5(3): 354–359. Dostupné z DOI: <http://dx.doi.org/10.1161/CIRCGENETICS.111.962456>.

44.  Umans-Eckenhausen MA, Defesche JC et al. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 2001; 357(9251):165–168. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(00)03587-X>.

49.  Umans-Eckenhausen MA, Defesche JC, van Dam MJ et al. Long-term compliance with lipid-lowering medication after genetic screening for familial hypercholesterolemia. Arch Intern Med 2003; 163(1): 65–68. Dostupné z DOI: <http://dx.doi.org/10.1001/archinte.163.1.65>.

50.  Leren TP, Manshaus T, Skovholt U et al. Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. Semin Vasc Med 3004; 4(1): 75–85. Dostupné z DOI: <http://dx.doi.org/10.1055/s-2004–822989>.

73.  Vuorio A, Docherty KF, Humphries SE et al. Statin treatment of children with familial hypercholesterolemia – trying to balance incomplete evidence of long-term safety and clinical accountability: are we approaching a consensus? Atherosclerosis 2013; 226(2): 315–320. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.03>.

76.  Marteau T, Senior V, Humphries SE et al. Psychological impact of genetic testing for familial hypercholesterolemia within a previously aware population: a randomized controlled trial. Am J Med Genet Part A 2004; 128A(3): 285–293. Dostupné z DOI: <http://dx.doi.org/10.1002/ajmg.a.30102>.

77.  Jenkins N, Lawton J, Douglas M et al. How do index patients participating in genetic screening programmes for familial hypercholesterolemia (FH) interpret their DNA results? A UK-based qualitative interview study. Patient Educ Counseling 2013; 90(3): 372–377. Dostupné z DOI: <http://dx.doi.org/10.1016/j.pec.2011.09.002>.

78.  Hallowell N, Jenkins N, Douglas M et al. A qualitative study of patients’ perceptions of the value of molecular diagnosis for familial hypercholesterolemia (FH). J Commun Genet 2017; 8(1):45–52. Dostupné z DOI: <http://dx.doi.org/10.1007/s12687–016–0286–0>.

82.  Iacocca MA, Hegele RA. Recent advances in genetic testing for familial hypercholesterolemia. Expert Rev Mol Diagn 2017; 17(7): 641–651. Dostupné z DOI: <http://dx.doi.org/10.1080/14737159.2017.1332997>.

83.  Taylor A, Wang D, Patel K et al. Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot CASCADE project. Clin Genet 2010; 77(6): 572–580. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1399–0004.2009.01356.x>.

84.  Humphries SE, Whittall RA, Hubbart CS et al. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet 2006; 43(12): 943–949. Dostupné z DOI: <http://dx.doi.org/10.1136/jmg.2006.038356>.

85.  Chora JR, Medeiros AM, Alves AC et al. Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. Genet Med 2018; 20(6):591–598. Dostupné z DOI: <http://dx.doi.org/10.1038/gim.2017.151>.

86.  Dedoussis GV, Schmidt H, Genschel J. LDL-receptor mutations in Europe. Hum Mutat 2004; 24(6): 443–459. Dostupné z DOI: <http://dx.doi.org/10.1002/humu.20105>.

87.  Leigh S, Futema M. Whittall R et al. The UCL low-density lipoprotein receptor gene variant database: pathogenicity update. J Med Genet 2017; 54(4): 217–223. Dostupné z DOI: <http://dx.doi.org/10.1136/jmedgenet-2016–104054.

88.  Taylor A, Martin B, Wang D et al. Multiplex ligation-dependent probe amplification analysis to screen for deletions and duplications of the LDLR gene in patients with familial hypercholesterolaemia. Clin Genet 2009; 76(1): 69–75. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1399–0004.2009.01168.x>.

89.  Bertolini S, Pisciotta L, Rabacchi C et al. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis 2013; 227(2): 342–348. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosis.2013.01.007>.

90.  Goldmann R, Tichy L, Freiberger T et al. Genomic characterization of large rearrangements of the LDLR gene in Czech patients with familial hypercholesterolemia. BMC Med Genet 2010; 11: 115. Dostupné z DOI: <http://dx.doi.org/10.1186/1471–2350–11–115>.

91.  Myant NB. Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia. Atherosclerosis 1993; 104(1–2): 1–18. Dostupné z DOI: <http://dx.doi.org/10.1016/0021–9150(93)90171-p>.

92.  Myant NB, Forbes SA, Day IN et al. Estimation of the age of the ancestral arginine3500-->glutamine mutation in human apoB-100. Genomics 1997; 45(1): 78–87. Dostupné z DOI: <http://dx.doi.org/10.1006/geno.1997.4898>.

93.  Andersen LH, Miserez AR, Ahmad Z et al. Familial defective apolipoprotein B-100: a review. J Clin Lipidol 2016; 10(6): 1297–1302. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacl.2016.09.009>.

101. Amor-Salamanca A, Castillo S, Gonzalez-Vioque E et al. Genetically confirmed familial hypercholesterolemia in patients with acute coronary syndrome. J Am Coll Cardiol 2017; 70(14): 1732–1740. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacc.2017.08.009>.

102. Silva P, Jannes CE, Oliveira TG et al. Evaluation of clinical and laboratory parameters used in the identification of index cases for genetic screening of familial hypercholesterolemia in Brazil. Atherosclerosis 2017; 263: 257–262. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.917>.

103. Haralambos K, Whatley SD, Edwards R et al. Clinical experience of scoring criteria for familial hypercholesterolaemia (FH) genetic testing in Wales. Atherosclerosis 2015; 240(1): 190–196. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosis.2015.03.003>.

104. van der Graaf A, Avis HJ, Kusters DM et al. Molecular basis of autosomal dominant hypercholesterolemia assessment in a large cohort of hypercholesterolemic children. Circulation 2011; 123(11): 1167–1173. Dostupné z DOI: <http://dx.doi.org/10.1161/CIRCULATIONAHA.110.979450>.

105. Perak AM, Ning H, de Ferranti SD et al. Long-term risk of atherosclerotic cardiovascular disease in US adults with the familial hypercholesterolemia phenotype. Circulation 2016; 134(1): 9–19. Dostupné z DOI: <http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022335>.

107. Wang J, Dron JS, Ban MR et al. Polygenic versus monogenic causes of hypercholesterolemia ascertained clinically. Arterioscler Thromb Vasc Biol 2016; 36(12): 2439–2445. Dostupné z DOI: <http://dx.doi.org/10.1161/ATVBAHA.116.308027>.

110. D’Erasmo L, Minicocci I, Nicolucci A et al. Autosomal recessive hypercholesterolemia: long-term cardiovascular outcomes. J Am Coll Cardiol 2018; 71(3): 279–288.Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacc.2017.11.028>.

111. Awan Z, Choi HY, Stitziel N et al. APOE p.Leu167del mutation in familial hypercholesterolemia. Atherosclerosis 2013; 231(2): 218–222. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosis.2013.09.007>.

112. Hegele RA, Ban MR, Cao H et al. Targeted next-generation sequencing in monogenic dyslipidemias. Curr Opin Lipidol 2015; 26(2): 103–113. Dostupné z DOI: <http://dx.doi.org/10.1097/MOL.0000000000000163>.

113. Chora JR, Alves AC, Medeiros AM et al. Lysosomal acid lipase deficiency: a hidden disease among cohorts of familial hypercholesterolemia? J Clin Lipidol 2017; 11(2): 477–484.e2. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacl.2016.11.002>.

114. Berge KE, Tian H, Graf GA et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000; 290(5497): 1771–1775. Dostupné z DOI: <http://dx.doi.org/10.1126/science.290.5497.1771>.

115. Stitziel NO, Fouchier SW, Sjouke B et al. Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia. Arterioscler Thromb Vasc Biol 2013; 33(12): 2909–2914. Dostupné z DOI: <http://dx.doi.org/10.1161/ATVBAHA.113.302426>.

116. Teslovich TM, Musunuru K, Smith AV et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010; 466(7307): 707–713. Dostupné z DOI: <http://dx.doi.org/10.1038/nature09270>.

117. Ellis KL, Pang J, Chan DC et al. Familial combined hyperlipidemia and hyperlipoprotein(a) as phenotypic mimics of familial hypercholesterolemia: frequencies, associations and predictions. J Clin Lipidol 2016; 10(6):1329–1337.e3. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacl.2016.08.011>.

127. Clayton EW. Why the Americans with Disabilities Act Matters for genetics. JAMA 2015; 313(22): 2225–2226. Dostupné z DOI: <http://dx.doi.org/10.1001/jama.2015.3419>.

128. Hopkins PN, Lane SR. Genotype-guided diagnosis in familial hypercholesterolemia: clinical management and concerns. Curr Opin Lipidol 2017; 28(2): 144–151. Dostupné z DOI: <http://dx.doi.org/10.1097/MOL.0000000000000397>.

129. Sturm AC. The role of genetic counselors for patients with familial hypercholesterolemia. Curr Genet Med Rep 2014; 2(2): 68–74. Dostupné z DOI: <http://dx.doi.org/10.1007/s40142–014–0036–8>.

Labels
Angiology Diabetology Internal medicine Cardiology General practitioner for adults

Article was published in

Athero Review

Issue 3

2020 Issue 3

Most read in this issue

This topic is also in:


Login
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account