Imperial College London



Improving the global care of familial hypercholesterolaemia: starting the ball rolling.Kausik K Raya,b, Gerald F Wattsc,d,eAffiliations:Imperial Centre for Cardiovascular Disease Prevention (ICCP), Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United KingdomCoordinating Centre for EAS FH Studies Collaboration, Imperial College London, London, United KingdomSchool of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, AustraliaLipid Disorders Clinic, Cardiometabolic Services, Department of Cardiology, Royal Perth Hospital, Perth, AustraliaFamilial Hypercholesterolaemia Australasia NetworkKey Words: Familial hypercholesterolaemia; global collaboration; registries.Corresponding authorsGerald F Wattsgerald.watts@uwa.edu.auKausik K Rayk.ray@imperial.ac.ukIn 2013, a European Atherosclerosis Society (EAS) consensus panel concluded that familial hypercholesterolaemia (FH) was underdiagnosed and undertreated ADDIN EN.CITE <EndNote><Cite><Author>Nordestgaard</Author><Year>2013</Year><RecNum>5701</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>5701</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1404790641">5701</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nordestgaard, BG</author><author>Chapman, MJ</author><author>Humphries, SE</author><author>Ginsberg, HN</author><author>Masana, L</author><author>Descamps, OS</author><author>Wiklund, O</author><author>Hegele, RA</author><author>Raal, FJ</author><author>Defesche, JC</author><author>Wiegman, A</author><author>Santos, RD</author><author>Watts, GF</author><author>Parhofer, KG</author><author>Kees Hovingh, G</author><author>Kovanen, PT</author><author>Boileau, C</author><author>Averna, M</author><author>Boren, J</author><author>Bruckert, E</author><author>Catapano, AL</author><author>Kuivenhoven, JA</author><author>Pajukanta, P</author><author>Ray, K</author><author>Stalenhoef, AF</author><author>Stroes, E</author><author>Taskinen, MR</author><author>Tybjaerg-Hansen, A</author><author>for the European Atherosclerosis Society Consensus Panel</author></authors></contributors><titles><title>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)</title><secondary-title>Eur Heart J</secondary-title></titles><periodical><full-title>European Heart Journal</full-title><abbr-1>Eur. Heart J.</abbr-1><abbr-2>Eur Heart J</abbr-2></periodical><pages>3478 - 3490</pages><volume>34</volume><number>45</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>1. Supported by international evidencePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXR0czwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 2-5, the expert panel also recognised the worldwide shortfall of data on the care of FH.The Familial Hypercholesterolaemia Studies CollaborationTo address this important demand, the Familial Hypercholesterolaemia Studies Collaboration (FHSC) was established under the auspices of the EAS in 2015. The primary aim of the FHSC is to improve global knowledge of the care of FH patients through the acquisition, curation and analysis of big data within a robust registry framework. The first publication hailed ‘a call to arms’PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWxsZWpvLVZhejwvQXV0aG9yPjxZZWFyPjIwMTU8L1ll

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ADDIN EN.CITE.DATA 6 to buttress critical gaps in the care of FH. The mission, aims and technical aspects of the FHSC registry have been publishedPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWxsZWpvLVZhejwvQXV0aG9yPjxZZWFyPjIwMTY8L1ll

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ADDIN EN.CITE.DATA 7. The registry harbours the largest global dataset on FH, derived from 70 countries across 6 continents.This issue of Atherosclerosis includes a thematic series of 41 peer-assessed articles on diverse aspects of the care of FH, including the overview FHSC report and 5 invited reviews from leading experts in the field.Overview report from the FHSCThe opening article from the FHSC presents the outcome of a survey relating to awareness, prevalence, management and treatment of FH across member countries. The report highlights a general lack of information on the prevalence of FH in most of the participating countries, and universally low rates of identification ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-01066</Author><RecNum>8047</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>8047</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536131349">8047</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-01066</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>8. Where data are available, figures concur with contemporary estimates ADDIN EN.CITE <EndNote><Cite><Author>Akioyamen</Author><Year>2017</Year><RecNum>7319</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>7319</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1504586747">7319</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Akioyamen, Leo E</author><author>Genest, Jacques</author><author>Shan, Shubham D</author><author>Reel, Rachel L</author><author>Albaum, Jordan M</author><author>Chu, Anna</author><author>Tu, Jack V</author></authors></contributors><titles><title>Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis</title><secondary-title>BMJ Open</secondary-title></titles><periodical><full-title>BMJ Open</full-title></periodical><pages>e016461</pages><volume>7</volume><number>9</number><dates><year>2017</year></dates><urls></urls><electronic-resource-num>10.1136/bmjopen-2017-016461</electronic-resource-num></record></Cite></EndNote>9. The distribution of plasma cholesterol in the community and specific characteristics, such as gene founder effects and consanguinity, and population sampling methods clearly influence the frequency estimates and detection rates of FH ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-01066</Author><RecNum>8047</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>8047</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536131349">8047</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-01066</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>8. The survey shows that the Dutch Lipid Network Score is the most popular diagnostic tool, followed by Simon Broome and MEDPED; a minority of countries use modified criteriaPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaG91PC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 2, 10, highlighting the need for country-specific tools for FH diagnosis. Importantly, a critical observation is the lack of resources and funding to support best clinical practice in caring for FH. Genetic testing is not universally available and is used mostly to confirm clinical diagnosis; however, in the majority of cases, genetic testing is only self-funded or available in the context of research. About 30% of the countries surveyed offer genetic cascade screening mostly on a regional basis, with only a few at national level, but the funding formula is uncertain. Pharmacotherapies for manging FH are implemented in all countries, but are not universally reimbursed, re-imbursement criteria varying widely. High intensity statins are the standard of care, usually with add-on ezetimibe; in 4 countries, however, ezetimibe is not available. About 70% of the countries report availability of PCSK9-inhibitors, but use is restricted; 60% offer lipoprotein apheresis, but this is limited to one centralised or a few reference centres ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-01066</Author><RecNum>8047</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>8047</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536131349">8047</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-01066</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>8.EpidemiologyThe subsequent papers add to the evolving corpus of information referred to above. Several countries report that the community prevalence of FH is 2-fold greater than previously recognisedPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BVEgtRC0xOC0wMDM4NDwvQXV0aG9yPjxSZWNOdW0+ODA1

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ADDIN EN.CITE.DATA 11-16. This makes FH a public health issue that needs to be accordingly addressed. An expert review accepts the higher frequency of FH, but cautions that the data need to account for the method of diagnosis, ascertainment bias, gene founder effects, and consanguinity ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00487</Author><RecNum>8082</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>8082</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536138172">8082</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00487</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>17.Several of the clinical surveys indicated that FH remains largely undiagnosed and untreatedPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BVEgtRC0xOC0wMDM4NTwvQXV0aG9yPjxSZWNOdW0+ODA1

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ADDIN EN.CITE.DATA 12, 18-27, despite meeting all the classical criteria for screening. The prevalence of definite FH is probably 5-fold higher among younger patients with an acute coronary syndrome ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00397</Author><RecNum>8063</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>8063</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536133210">8063</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00397</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>28 and protocols for linking the detection of such patients to follow-up in specialist clinics and the cascade testing of relatives for FH have been proposed ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00294</Author><RecNum>8051</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>8051</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536132085">8051</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00294</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>29. The universal screening of children for FH has been championed in the UK and US ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00389</Author><RecNum>8059</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>8059</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536132572">8059</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00389</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>30, but only implemented and shown to be efficacious in Slovenia ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00414</Author><RecNum>8075</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>8075</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536135603">8075</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00414</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>31. Universal screening of children, with reverse cascade testing of parents, has recently been shown to be cost-effective and deserves more consideration ADDIN EN.CITE <EndNote><Cite><Author>McKay</Author><Year>2018</Year><RecNum>8042</RecNum><DisplayText><style face="superscript">32</style></DisplayText><record><rec-number>8042</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536030328">8042</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McKay, Ailsa J</author><author>Hogan, Helen</author><author>Humphries, Steve E</author><author>Marks, Dalya</author><author>Ray, Kausik K</author><author>Miners, Alec</author></authors></contributors><titles><title>Universal screening at age 1–2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: A cost-utility analysis</title><secondary-title>Atherosclerosis</secondary-title></titles><periodical><full-title>Atherosclerosis</full-title><abbr-1>Atherosclerosis</abbr-1><abbr-2>Atherosclerosis</abbr-2></periodical><pages>434-443</pages><volume>275</volume><dates><year>2018</year></dates><isbn>0021-9150</isbn><urls></urls></record></Cite></EndNote>32. In WHO low-to-middle income countries, reverse cascade testing from a child with HoFH is an effective method of detecting high-risk family members ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00221</Author><RecNum>8048</RecNum><DisplayText><style face="superscript">33</style></DisplayText><record><rec-number>8048</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536131555">8048</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00221</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>33. Few reports give attention to the role of primary care in screening. This last topic is well reviewed by Brett et al ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00554</Author><RecNum>8087</RecNum><DisplayText><style face="superscript">34</style></DisplayText><record><rec-number>8087</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536138598">8087</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00554</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>34 who emphasized the value of opportunistic screening employing electronic data extraction tools, as exemplified by a report from Lithuania ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00396</Author><RecNum>8062</RecNum><DisplayText><style face="superscript">35</style></DisplayText><record><rec-number>8062</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536133163">8062</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00396</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>35. 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ADDIN EN.CITE.DATA 1, 2, 34, 36.Diagnostic toolsWhilst the Dutch Lipid Clinic Network criteria are most popular for diagnosing FH ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-01066</Author><RecNum>8047</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>8047</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536131349">8047</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-01066</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>8, but lack of information assails making an accurate diagnosis of FH ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00500</Author><RecNum>8083</RecNum><DisplayText><style face="superscript">37</style></DisplayText><record><rec-number>8083</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536138209">8083</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00500</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>37. Concordance with the Simon Broome and MED-PED criteria can also be moderate to lowPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BaG1hZDwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 38. The Canadian network has therefore developed a simple and robust algorithm for diagnosing FH ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00352</Author><RecNum>8052</RecNum><DisplayText><style face="superscript">39</style></DisplayText><record><rec-number>8052</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536132139">8052</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00352</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>39. Whether this could provide a new standard diagnosis for FH remains to be verified. Country-specific criteria for FH are essential, particularly since there can be wide geographical variation (e.g. Europe and US vs Asia) in the population percentile values for LDL-cholesterol concentrations ADDIN EN.CITE <EndNote><Cite><Author>Zhou</Author><Year>2016</Year><RecNum>6358</RecNum><DisplayText><style face="superscript">8, 10</style></DisplayText><record><rec-number>6358</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1471258303">6358</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhou, Mengge</author><author>Zhao, Dong</author></authors></contributors><titles><title>Familial Hypercholesterolemia in Asian Populations</title><secondary-title>Journal of Atherosclerosis and Thrombosis</secondary-title></titles><periodical><full-title>Journal of Atherosclerosis and Thrombosis</full-title><abbr-1>J. Atheroscler. Thromb.</abbr-1></periodical><pages>539-549</pages><volume>23</volume><number>5</number><dates><year>2016</year></dates><urls></urls><electronic-resource-num>10.5551/jat.34405</electronic-resource-num></record></Cite><Cite><Author>ATH-D-18-01066</Author><RecNum>8047</RecNum><record><rec-number>8047</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536131349">8047</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-01066</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>8, 10. A practical definition of homozygous FH is also required ADDIN EN.CITE <EndNote><Cite><Author>Santos</Author><Year>2016</Year><RecNum>6349</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>6349</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1470882668">6349</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Santos, Raul D</author><author>Gidding, Samuel S</author><author>Hegele, Robert A</author><author>Cuchel, Marina A</author><author>Barter, Philip J</author><author>Watts, Gerald F</author><author>Baum, Seth J</author><author>Catapano, Alberico L</author><author>Chapman, M John</author><author>Defesche, Joep C</author></authors></contributors><titles><title>Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel</title><secondary-title>Lancet Diabetes &amp; Endocrinology</secondary-title></titles><periodical><full-title>Lancet Diabetes &amp; Endocrinology</full-title></periodical><pages>850–61</pages><volume>4</volume><number>10</number><dates><year>2016</year></dates><isbn>2213-8587</isbn><urls></urls></record></Cite></EndNote>4, noting the phenotypic diversity of the condition ADDIN EN.CITE <EndNote><Cite><Author>Raal</Author><Year>2016</Year><RecNum>8043</RecNum><DisplayText><style face="superscript">40</style></DisplayText><record><rec-number>8043</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536031221">8043</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Raal, Frederick J</author><author>Sjouke, Barbara</author><author>Hovingh, G Kees</author><author>Isaac, Barton F</author></authors></contributors><titles><title>Phenotype diversity among patients with homozygous familial hypercholesterolemia: a cohort study</title><secondary-title>Atherosclerosis</secondary-title></titles><periodical><full-title>Atherosclerosis</full-title><abbr-1>Atherosclerosis</abbr-1><abbr-2>Atherosclerosis</abbr-2></periodical><pages>238-244</pages><volume>248</volume><dates><year>2016</year></dates><isbn>0021-9150</isbn><urls></urls></record></Cite></EndNote>40.Genetic testingBest practice in precision medicine requires that the diagnosis of FH be confirmed genetically ADDIN EN.CITE <EndNote><Cite><Author>Sturm</Author><Year>2018</Year><RecNum>8019</RecNum><DisplayText><style face="superscript">41</style></DisplayText><record><rec-number>8019</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1534404340">8019</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sturm, Amy C</author><author>Knowles, Joshua W</author><author>Gidding, Samuel S</author><author>Ahmad, Zahid S</author><author>Ahmed, Catherine D</author><author>Ballantyne, Christie M</author><author>Baum, Seth J</author><author>Bourbon, Mafalda</author><author>Carrié, Alain</author><author>Cuchel, Marina</author></authors></contributors><titles><title>Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel</title><secondary-title>Journal of the American College of Cardiology</secondary-title></titles><periodical><full-title>Journal of the American College of Cardiology</full-title><abbr-1>J. Am. Coll. Cardiol.</abbr-1><abbr-2>J Am Coll Cardiol</abbr-2></periodical><pages>662-680</pages><volume>72</volume><number>6</number><dates><year>2018</year></dates><isbn>0735-1097</isbn><urls></urls></record></Cite></EndNote>41. Several countries have therefore undertaken their own genetic studies, supported in some cases by international expertsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BVEgtRC0xOC0wMDIyMTwvQXV0aG9yPjxSZWNOdW0+ODA0

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ADDIN EN.CITE.DATA 11, 16, 31, 33, 37, 42-45. Genetic testing is important in countries with high rates of consanguinity ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00386</Author><RecNum>8058</RecNum><DisplayText><style face="superscript">42</style></DisplayText><record><rec-number>8058</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536132513">8058</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00386</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>42. Next generation sequencing permits the detection of a wider spectrum of mutations ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00384</Author><RecNum>8056</RecNum><DisplayText><style face="superscript">11, 16, 44, 45</style></DisplayText><record><rec-number>8056</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536132372">8056</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00384</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite><Cite><Author>ATH-D-18-00413</Author><RecNum>8074</RecNum><record><rec-number>8074</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536135307">8074</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00413</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite><Cite><Author>ATH-D-18-00427</Author><RecNum>8077</RecNum><record><rec-number>8077</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536135725">8077</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00427</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite><Cite><Author>ATH-D-18-00448</Author><RecNum>8079</RecNum><record><rec-number>8079</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536135884">8079</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00448</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>11, 16, 44, 45 that not only facilitate a definitive diagnosis of FH, but may also confirm polygenic hypercholestrerolaemia; this molecular diagnosis may predict a more adverse prognosis in FH or when isolated may be used to ration cascade testing ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00501</Author><RecNum>8086</RecNum><DisplayText><style face="superscript">46</style></DisplayText><record><rec-number>8086</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536138561">8086</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00501</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>46. Genetic testing is acceptable and does not impair quality of life, which is more likely consequent on co-existent morbidities in FH ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00359</Author><RecNum>8053</RecNum><DisplayText><style face="superscript">47</style></DisplayText><record><rec-number>8053</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536132186">8053</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00359</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>47.Risk stratificationThe clinical expression of FH is variable and cardiovascular (CV) risk equations have been described ADDIN EN.CITE <EndNote><Cite><Author>Pérez de Isla</Author><Year>2017</Year><RecNum>6969</RecNum><DisplayText><style face="superscript">48</style></DisplayText><record><rec-number>6969</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1492566533">6969</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pérez de Isla, Leopoldo</author><author>Alonso, Rodrigo</author><author>Mata, Nelva</author><author>Fernández-Pérez, Cristina</author><author>Mu?iz, Ovidio</author><author>Díaz-Díaz, José Luis</author><author>Saltijeral, Adriana</author><author>Fuentes-Jiménez, Francisco J.</author><author>de Andrés, Raimundo</author><author>Zambón, Daniel</author><author>Piedecausa, Mar</author><author>Cepeda, José María</author><author>Mauri, Marta</author><author>Galiana, Jesús</author><author>Brea, ?ngel</author><author>Sanchez Mu?oz-Torrero, Juan F.</author><author>Padró, Teresa</author><author>Argueso, Rosa</author><author>Miramontes-González, José Pablo</author><author>Badimón, Lina</author><author>Santos, Raúl D.</author><author>Watts, Gerald F.</author><author>Mata, Pedro</author></authors></contributors><titles><title>Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1><abbr-2>Circulation</abbr-2></periodical><pages>2133-2144</pages><volume>135</volume><dates><year>2017</year></dates><urls></urls><electronic-resource-num>10.1161/circulationaha.116.024541</electronic-resource-num></record></Cite></EndNote>48. 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ADDIN EN.CITE.DATA 18, 20, 23-26, 49. Smoking remains a major driver of CV risk across all continents ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00282</Author><RecNum>8050</RecNum><DisplayText><style face="superscript">25, 49</style></DisplayText><record><rec-number>8050</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536132017">8050</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00282</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite><Cite><Author>ATH-D-18-00450</Author><RecNum>8080</RecNum><record><rec-number>8080</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536135924">8080</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00450</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite><Cite><Author>ATH-D-18-00282</Author><RecNum>8050</RecNum><record><rec-number>8050</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536132017">8050</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00282</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>25, 49, providing a major mandate for coronary prevention in FH. Diabetes and hypertension are also major priorities and the prevention of obesity a critical lifestyle objective in children with FH. The roles of Lp(a) ADDIN EN.CITE <EndNote><Cite><Author>Alonso</Author><Year>2014</Year><RecNum>5464</RecNum><DisplayText><style face="superscript">50</style></DisplayText><record><rec-number>5464</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1399433561">5464</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Alonso, Rodrigo</author><author>Andres, Eduardo</author><author>Mata, Nelva</author><author>Fuentes-Jiménez, Francisco</author><author>Badimón, Lina</author><author>López-Miranda, José</author><author>Padró, Teresa</author><author>Mu?iz, Ovidio</author><author>Díaz-Díaz, Jose Luis</author><author>Mauri, Marta</author></authors></contributors><titles><title>Lipoprotein (a) levels in Familial Hipercholesterolaemia: an important predictor for cardiovascular disease independent of the type of LDL-receptor mutation</title><secondary-title>Journal of the American College of Cardiology</secondary-title></titles><periodical><full-title>Journal of the American College of Cardiology</full-title><abbr-1>J. Am. Coll. Cardiol.</abbr-1><abbr-2>J Am Coll Cardiol</abbr-2></periodical><pages>1982-1989</pages><volume>63</volume><number>19</number><dates><year>2014</year></dates><isbn>0735-1097</isbn><urls></urls></record></Cite></EndNote>50, cardiac imaging ADDIN EN.CITE <EndNote><Cite><Author>Sijbrands</Author><Year>2015</Year><RecNum>6151</RecNum><DisplayText><style face="superscript">51</style></DisplayText><record><rec-number>6151</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1445940410">6151</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sijbrands, Eric JG</author><author>Nieman, Koen</author><author>Budoff, Matthew J</author></authors></contributors><titles><title>Cardiac computed tomography imaging in familial hypercholesterolemia: implications for therapy and clinical trials</title><secondary-title>Current Opinion in Lipidology</secondary-title></titles><periodical><full-title>Current Opinion in Lipidology</full-title><abbr-1>Curr. Opin. Lipidol.</abbr-1><abbr-2>Curr Opin Lipidol</abbr-2></periodical><pages>586–592</pages><volume>26</volume><number>6</number><dates><year>2015</year></dates><isbn>0957-9672</isbn><urls></urls></record></Cite></EndNote>51 and genetic testing ADDIN EN.CITE <EndNote><Cite><Author>Sturm</Author><Year>2018</Year><RecNum>8019</RecNum><DisplayText><style face="superscript">41</style></DisplayText><record><rec-number>8019</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1534404340">8019</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sturm, Amy C</author><author>Knowles, Joshua W</author><author>Gidding, Samuel S</author><author>Ahmad, Zahid S</author><author>Ahmed, Catherine D</author><author>Ballantyne, Christie M</author><author>Baum, Seth J</author><author>Bourbon, Mafalda</author><author>Carrié, Alain</author><author>Cuchel, Marina</author></authors></contributors><titles><title>Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel</title><secondary-title>Journal of the American College of Cardiology</secondary-title></titles><periodical><full-title>Journal of the American College of Cardiology</full-title><abbr-1>J. Am. Coll. Cardiol.</abbr-1><abbr-2>J Am Coll Cardiol</abbr-2></periodical><pages>662-680</pages><volume>72</volume><number>6</number><dates><year>2018</year></dates><isbn>0735-1097</isbn><urls></urls></record></Cite></EndNote>41 in risk prediction are increasingly being recognised, but were not specifically covered in this first cluster of country reports. Lp(a) evidently needs to be accounted for when making the phenotypic diagnosis of FH ADDIN EN.CITE <EndNote><Cite><Author>Langsted</Author><Year>2016</Year><RecNum>6586</RecNum><DisplayText><style face="superscript">52</style></DisplayText><record><rec-number>6586</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1484797101">6586</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Langsted, Anne</author><author>Kamstrup, Pia R.</author><author>Benn, Marianne</author><author>Tybj?rg-Hansen, Anne</author><author>Nordestgaard, B?rge G.</author></authors></contributors><titles><title>High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study</title><secondary-title>The Lancet Diabetes &amp; Endocrinology</secondary-title></titles><periodical><full-title>The Lancet Diabetes &amp; Endocrinology</full-title></periodical><pages>577-587</pages><volume>4</volume><number>7</number><dates><year>2016</year><pub-dates><date>7//</date></pub-dates></dates><isbn>2213-8587</isbn><urls><related-urls><url>(16)30042-0</electronic-resource-num></record></Cite></EndNote>52 and its complex with PCSK9 in plasma ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00410</Author><RecNum>8071</RecNum><DisplayText><style face="superscript">53</style></DisplayText><record><rec-number>8071</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536135171">8071</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00410</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>53 could partly explain the reduction in Lp(a) with PCSK9 mAbs against background statin therapy ADDIN EN.CITE <EndNote><Cite><Author>Watts</Author><Year>2018</Year><RecNum>7758</RecNum><DisplayText><style face="superscript">54</style></DisplayText><record><rec-number>7758</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1521617153">7758</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Watts, Gerald F</author><author>Chan, Dick C</author><author>Somaratne, Ransi</author><author>Wasserman, Scott M</author><author>Scott, Rob</author><author>Marcovina, Santica M</author><author>Barrett, P Hugh R</author></authors></contributors><titles><title>Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with evolocumab on lipoprotein (a) particle kinetics</title><secondary-title>European Heart Journal</secondary-title></titles><periodical><full-title>European Heart Journal</full-title><abbr-1>Eur. 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Pn==

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Pn==

ADDIN EN.CITE.DATA 57, 58. The ideal LDL-targets for FH patients may require revision in light of new clinical outcome trials with PCSK9 inhibitors. Current lipid management guidelines will need updating in 2019PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5kbWVzc2VyPC9BdXRob3I+PFllYXI+MjAxODwvWWVh

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ADDIN EN.CITE.DATA 55, 59.Dedicated clinical services for FH can evidently achieve better treatment outcomes in FHPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BVEgtRC0xOC0wMDM2NjwvQXV0aG9yPjxSZWNOdW0+ODA1

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ADDIN EN.CITE.DATA 22, 25-27, 31. In low-to-middle income countries there is a major need to improve the care for severe FH ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00221</Author><RecNum>8048</RecNum><DisplayText><style face="superscript">33</style></DisplayText><record><rec-number>8048</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536131555">8048</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00221</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>33 and international advocacy for government funding for apheresis and new therapies is paramount. However, even in countries where apheresis is funded ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00450</Author><RecNum>8080</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>8080</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536135924">8080</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00450</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>25, homozygous FH patients remain non-receptive to this form of therapy. This emphasizes the importance of improving physician training and expertise and addressing patient perceptions and beliefs about treatment ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00277</Author><RecNum>8049</RecNum><DisplayText><style face="superscript">56</style></DisplayText><record><rec-number>8049</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536131886">8049</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00277</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>56. The optimal management of FH in pregnancy needs further delineation, but preliminary data from a selected series in South Africa suggests that statins may be used safely from the third or fourth month of pregnancy ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00379</Author><RecNum>8055</RecNum><DisplayText><style face="superscript">60</style></DisplayText><record><rec-number>8055</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536132321">8055</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00379</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>60. Lipoprotein apheresis, however, remains a cornerstone of management of women with FH and coronary artery disease during pregnancy ADDIN EN.CITE <EndNote><Cite><Author>Stefanutti</Author><Year>2017</Year><RecNum>7353</RecNum><DisplayText><style face="superscript">61</style></DisplayText><record><rec-number>7353</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1506324477">7353</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stefanutti, Claudia</author><author>Julius, Ulrich</author><author>Watts, Gerald F.</author><author>Harada-Shiba, Mariko</author><author>Cossu, Maria</author><author>Schettler, Volker J.</author><author>De Silvestro, Giustina</author><author>Soran, Handrean</author><author>Van Lennep, Jeanine Roeters</author><author>Pisciotta, Livia</author><author>Kl?r, Hans U.</author><author>Widhalm, Kurt</author><author>Moriarty, Patrick M.</author></authors></contributors><titles><title>Toward an international consensus—Integrating lipoprotein apheresis and new lipid-lowering drugs</title><secondary-title>Journal of Clinical Lipidology</secondary-title></titles><periodical><full-title>Journal of Clinical Lipidology</full-title><abbr-1>J. Clin. Lipidol.</abbr-1><abbr-2>J Clin Lipidol</abbr-2></periodical><pages>858-871.e3</pages><volume>11</volume><number>4</number><keywords><keyword>Dyslipidemia</keyword><keyword>Lipoprotein apheresis</keyword><keyword>Familial hypercholesterolemia</keyword><keyword>Lp(a) hyperlipoproteinemia</keyword><keyword>MTP inhibition</keyword><keyword>PCSK9 inhibition</keyword><keyword>HDL mimetic</keyword><keyword>LDL-cholesterol</keyword><keyword>Lipoproteins</keyword></keywords><dates><year>2017</year><pub-dates><date>2017/07/01/</date></pub-dates></dates><isbn>1933-2874</isbn><urls><related-urls><url> of community care Models of care for FH should ideally be integrated across medical disciplines ADDIN EN.CITE <EndNote><Cite><Author>Watts</Author><Year>2014</Year><RecNum>5373</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>5373</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1390529859">5373</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Watts, Gerald F</author><author>Gidding, Samuel</author><author>Wierzbicki, Anthony S</author><author>Toth, Peter P</author><author>Alonso, Rodrigo</author><author>Brown, W Virgil</author><author>Bruckert, Eric</author><author>Defesche, Joep</author><author>Lin, Khoo Kah</author><author>Livingston, Michael</author></authors></contributors><titles><title>Integrated Guidance on the Care of Familial Hypercholesterolaemia from the International FH Foundation</title><secondary-title>International Journal of Cardiology</secondary-title></titles><periodical><full-title>International Journal of Cardiology</full-title><abbr-1>Int. J. Cardiol.</abbr-1><abbr-2>Int J Cardiol</abbr-2></periodical><pages>309-325</pages><volume>171</volume><number>3</number><dates><year>2014</year></dates><isbn>0167-5273</isbn><urls></urls></record></Cite></EndNote>2. International guidelines recommend that most patients should be managed in primary carePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXR0czwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 1-3, noting that FH is a public health issue that accordingly needs addressing through several approaches to screening in the community ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00554</Author><RecNum>8087</RecNum><DisplayText><style face="superscript">34</style></DisplayText><record><rec-number>8087</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536138598">8087</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00554</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>34. While general practitioners, or family doctors, are ideally suited to detecting cases and caring for families with FH, their knowledge and practice remain suboptimal, but this can be partly remedied through dedicated vocational training and accreditation in FH ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00399</Author><RecNum>8065</RecNum><DisplayText><style face="superscript">62</style></DisplayText><record><rec-number>8065</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536133279">8065</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00399</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>62. Brett et al ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00554</Author><RecNum>8087</RecNum><DisplayText><style face="superscript">34</style></DisplayText><record><rec-number>8087</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536138598">8087</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00554</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>34 outline a comprehensive research agenda for primary care that encompasses several epidemiological, clinical (diagnostics, risk prediction, intervention trials), patient-centric and service design aspects of FH. This template can be adapted to set more general research priorities for the FHSC network.Patient support groups and networksPatient support groups and networks are essential for advocating critical improvements across the continuum of care of FH ADDIN EN.CITE <EndNote><Cite><Author>Watts</Author><Year>2014</Year><RecNum>5373</RecNum><DisplayText><style face="superscript">2, 30</style></DisplayText><record><rec-number>5373</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1390529859">5373</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Watts, Gerald F</author><author>Gidding, Samuel</author><author>Wierzbicki, Anthony S</author><author>Toth, Peter P</author><author>Alonso, Rodrigo</author><author>Brown, W Virgil</author><author>Bruckert, Eric</author><author>Defesche, Joep</author><author>Lin, Khoo Kah</author><author>Livingston, Michael</author></authors></contributors><titles><title>Integrated Guidance on the Care of Familial Hypercholesterolaemia from the International FH Foundation</title><secondary-title>International Journal of Cardiology</secondary-title></titles><periodical><full-title>International Journal of Cardiology</full-title><abbr-1>Int. J. Cardiol.</abbr-1><abbr-2>Int J Cardiol</abbr-2></periodical><pages>309-325</pages><volume>171</volume><number>3</number><dates><year>2014</year></dates><isbn>0167-5273</isbn><urls></urls></record></Cite><Cite><Author>ATH-D-18-00389</Author><RecNum>8059</RecNum><record><rec-number>8059</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536132572">8059</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00389</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>2, 30. Their value is well reviewed by an international consortium representing countries across Europe and North America ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-00389</Author><RecNum>8059</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>8059</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536132572">8059</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00389</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>30. The many achievements of these patient networks to date encompass government support for screening programmes, development of risk prediction tools, improvements in access to new therapies, support for patient registries, and recognition of a new ICD-10 code for FH.RegistriesRegistries are important not only to raise awareness of FH, but also to garner information necessary for clinical trials and audits, for education of registrants and healthcare professionals, and for health service research and policy making ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-01066</Author><RecNum>8047</RecNum><DisplayText><style face="superscript">8, 63</style></DisplayText><record><rec-number>8047</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536131349">8047</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-01066</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite><Cite><Author>ATH-D-18-00400</Author><RecNum>8066</RecNum><record><rec-number>8066</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536134932">8066</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-00400</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>8, 63. 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ADDIN EN.CITE.DATA 16, 18, 20, 21, 24-27, 31, 37, 39, 64. Through the FHSC there are abundant opportunities for enabling the development of fledgling registries. This could take the form of providing support and advice on registry governance, standardization of data elements, interoperability and expansion of platforms, with the ultimate aim of curating and analysing the highest quality big data required for maximising impact on the care of FH. Integration with other large international registries remains a future objectivePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZUdvbWE8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 48, 57, rmation gaps, more research and future reportsWhile a laudable initial set of papers are presented from the constituent member countries of the FHSC ADDIN EN.CITE <EndNote><Cite><Author>ATH-D-18-01066</Author><RecNum>8047</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>8047</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536131349">8047</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATH-D-18-01066</author></authors></contributors><titles></titles><dates></dates><urls></urls></record></Cite></EndNote>8, selected gaps in information and desirable data for future communications should be identified. More registry data are required on the care of children with FH ADDIN EN.CITE <EndNote><Cite><Author>Martin</Author><Year>2017</Year><RecNum>7295</RecNum><DisplayText><style face="superscript">36</style></DisplayText><record><rec-number>7295</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1503044316">7295</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martin, Andrew C</author><author>Gidding, Samuel S</author><author>Wiegman, Albert</author><author>Watts, Gerald F</author></authors></contributors><titles><title>Known and unknowns in the care of paediatric familial hypercholesterolaemia</title><secondary-title>Journal of Lipid Research</secondary-title></titles><periodical><full-title>Journal of Lipid Research</full-title><abbr-1>J. Lipid Res.</abbr-1><abbr-2>J Lipid Res</abbr-2></periodical><pages>1765-1776</pages><volume>58</volume><dates><year>2017</year></dates><isbn>0022-2275</isbn><urls></urls></record></Cite></EndNote>36, such an initiative being currently spearheaded by Humphries, Wiegman and colleaguesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYW1hc3dhbWk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFy

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ADDIN EN.CITE.DATA 66, 67. The population frequencies of FH need to be more systematically defined and communicated. This will require that the phenotypic diagnostic criteria for FH be both standardised and adjusted for specific countries. The less rigorous criteria adopted by some registries mean that many patients may not have ‘true’ FH ADDIN EN.CITE <EndNote><Cite><Author>Ellis</Author><Year>2016</Year><RecNum>6486</RecNum><DisplayText><style face="superscript">68</style></DisplayText><record><rec-number>6486</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1474960160">6486</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ellis, Katrina L</author><author>Pang, Jing</author><author>Chan, Dick C</author><author>Hooper, Amanda J</author><author>Bell, Damon A</author><author>Burnett, John R</author><author>Watts, Gerald F</author></authors></contributors><titles><title>Familial combined hyperlipidemia and hyperlipoprotein (a) as phenotypic mimics of familial hypercholesterolemia: Frequencies, associations and predictions</title><secondary-title>Journal of Clinical Lipidology</secondary-title></titles><periodical><full-title>Journal of Clinical Lipidology</full-title><abbr-1>J. Clin. Lipidol.</abbr-1><abbr-2>J Clin Lipidol</abbr-2></periodical><pages>1329–1337</pages><volume>10</volume><number>6</number><dates><year>2016</year></dates><isbn>1933-2874</isbn><urls></urls></record></Cite></EndNote>68. More information on methods of risk stratification and the specific roles of measuring Lp(a) and cardiovascular imaging would be welcomed from countries where these tests are feasible. Data on the frequency of statin intolerance in FH patients are highly relevant ADDIN EN.CITE <EndNote><Cite><Author>Rosenson</Author><Year>2017</Year><RecNum>7310</RecNum><DisplayText><style face="superscript">69</style></DisplayText><record><rec-number>7310</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1504512875">7310</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rosenson, Robert S.</author><author>Baker, Steven</author><author>Banach, Maciej</author><author>Borow, Kenneth M.</author><author>Braun, Lynne T.</author><author>Bruckert, Eric</author><author>Brunham, Liam R.</author><author>Catapano, Alberico L.</author><author>Elam, Marshall B.</author><author>Mancini, G. B. John</author><author>Moriarty, Patrick M.</author><author>Morris, Pamela B.</author><author>Muntner, Paul</author><author>Ray, Kausik K.</author><author>Stroes, Erik S.</author><author>Taylor, Beth A.</author><author>Taylor, Valerie H.</author><author>Watts, Gerald F.</author><author>Thompson, Paul D.</author></authors></contributors><titles><title>Optimizing Cholesterol Treatment in Patients With Muscle Complaints</title><secondary-title>Journal of the American College of Cardiology</secondary-title></titles><periodical><full-title>Journal of the American College of Cardiology</full-title><abbr-1>J. Am. Coll. Cardiol.</abbr-1><abbr-2>J Am Coll Cardiol</abbr-2></periodical><pages>1290-1301</pages><volume>70</volume><number>10</number><keywords><keyword>cardiovascular disease</keyword><keyword>low-density lipoprotein</keyword><keyword>myalgia</keyword><keyword>myopathy</keyword><keyword>statin intolerance</keyword></keywords><dates><year>2017</year><pub-dates><date>9/5/</date></pub-dates></dates><isbn>0735-1097</isbn><urls><related-urls><url>. Reports on patient-centric perceptions and the outcome of health economic evaluations of the models of care for FH from individual countries would in time be particularly apposite ADDIN EN.CITE <EndNote><Cite><Author>Norman</Author><Year>2016</Year><RecNum>6797</RecNum><DisplayText><style face="superscript">70</style></DisplayText><record><rec-number>6797</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1484800858">6797</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Norman, Richard</author><author>Watts, Gerald F</author><author>Weintraub, William</author><author>Gidding, Samuel S</author></authors></contributors><titles><title>Challenges in the health economics of familial hypercholesterolemia</title><secondary-title>Current Opinion in Lipidology</secondary-title></titles><periodical><full-title>Current Opinion in Lipidology</full-title><abbr-1>Curr. Opin. Lipidol.</abbr-1><abbr-2>Curr Opin Lipidol</abbr-2></periodical><pages>563-569</pages><volume>27</volume><number>6</number><dates><year>2016</year></dates><isbn>0957-9672</isbn><urls></urls></record></Cite></EndNote>70. There were only a handful of papers on homozygous FH, but this is will be more extensively covered by communications from the HoFH International Clinical Collaboration (HICC) registry headed by Raal, Hovingh and Cuchel ADDIN EN.CITE <EndNote><Cite><Author>Hartgers</Author><Year>2018</Year><RecNum>8045</RecNum><DisplayText><style face="superscript">71</style></DisplayText><record><rec-number>8045</rec-number><foreign-keys><key app="EN" db-id="5wtfz02r2tztezeex2m5rtdqv2r52x5wt02a" timestamp="1536034238">8045</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hartgers, M</author><author>Cuchel, M</author><author>Hovingh, GK</author><author>Blom, DJ</author><author>Raal, FJ</author></authors></contributors><titles><title>Clinical, demographic and genetic characteristics of homozygous familial hypercholesterolemia patients worldwide: Interim results from the hofh international clinical collaborators (HICC) registry</title><secondary-title>Atherosclerosis</secondary-title></titles><periodical><full-title>Atherosclerosis</full-title><abbr-1>Atherosclerosis</abbr-1><abbr-2>Atherosclerosis</abbr-2></periodical><volume>275</volume><dates><year>2018</year></dates><isbn>0021-9150</isbn><urls></urls></record></Cite></EndNote>71.Finally, global and country-specific models of care for FH will necessarily metamorphose as new evidence accrues from the scientific and clinical community of researchers. 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ADDIN EN.CITE.DATA 6 against the worldwide burden of cardiovascular disease imposed by under-detected and under-treated FH.Disclosures:Professor Ray reports personal fees from Abbvie, grants and personal fees from Amgen, personal fees from Astra Zeneca, grants and personal fees from Sanofi, grants and personal fees from Regeneron, grants and personal fees from MSD, grants and personal fees from Pfizer, personal fees from Medco, personal fees from Resverlogix, personal fees from Akcea, personal fees from Boehringer Ingelheim, personal fees from Novo Nordisk, personal fees from Takeda, personal fees from Kowa, personal fees from Cerenis, personal fees from Cipla, personal fees from Algorithm,? from Esperion,? outside the submitted work.Professor Watts reports research grants from Amgen, Sanofi and Regeneron, and honoraria for advisory boards from Amgen, Sanofi, Regeneron, Gemphire and Kowa, outside the submitted work.References: will need c. 50 refs ADDIN EN.REFLIST [1]Nordestgaard, B, Chapman, M, Humphries, S, 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;34:3478 - 3490.[2]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;171:309-325.[3]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.[4]Santos, RD, Gidding, SS, Hegele, RA, et al., Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel, Lancet Diabetes & Endocrinology, 2016;4:850–861.[5]Goldberg, AC, Robinson, JG, Cromwell, WC, et al., Future issues, public policy, and public awareness of Familial Hypercholesterolemias: Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia, J. Clin. 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