1 s2.0 S0146280622000482 Main

&
T Bibliometric Analysis of Familial

agedH1A
Hypercholesterolemia From 2011 to
2021TagedEn
T amin Weia, Yuanhui Hub, Guoxiu Liua, Siyu Lia,
agedPN
Guozhen Yuanb, Xintian Shoub, Xuesong Zhangb,
Jingjing Shib, and Huaqiang Zhaia*TagedEn
From the TagedPa School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing,
China and b Department of Cardiovascular Diseases, Guang’anmen Hospital, China Academy of
Chinese Medical Sciences, Beijing, China.TagedEn
TagedPAbstract: Familial Hypercholesterolemia (FH), an

autosomal dominant genetic disease, is increasingly
emerging as a global threat. To learn more about the
development of FH, 1 617 papers about FH and related
research were retrieved in the Web of Science Core
Collection from 2011 to 2021. Then, these publications
were scientometrically analyzed based on CiteSpace
and VOSviewer in terms of spatiotemporal distribu-
tion, author distribution, subject categories, topic dis-
tribution, and references. The results showed that
research on FH is at a stable stage. More FH research
has been conducted in developed countries, implying
the necessity for strengthening international coopera-
tion and exchanges. We have obtained scholars, insti-
tutions, relevant journals, and representative
literatures that play an important role in FH. The
research direction of FH is on the mechanisms of FH
and its complications, diagnosis, statin therapy, and
new lipid-lowering drug therapy. Care is the research
frontier in FH, and it is in an explosive period. (Curr
Probl Cardiol 2023;48:101151.)TagedEn
TagedEnConflict of Interest: The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Curr Probl Cardiol 2023;48:101151
0146-2806/$ see front matter
https://doi.org/10.1016/j.cpcardiol.2022.101151
TagedEnCurr Probl Cardiol, July 2023 1

TagedH1IntroductionTagedEn
&
F
amilial hypercholesterolemia (FH) is an autosomal dominant
hereditary disorder that is increasingly emerging as a global public
health concern.1 Based on dominant genetic characteristics, FH
are classified into homozygous familial hypercholesterolemia (HoFH) and
heterozygous hypercholesterolemia (HeFH). In the Lebanese FH family,
Khachadurian was the first description of the heritability of FH in 1964.2
The global incidence of FH is about 1 of 250 of the general population,
with roughly 14-34 million people having FH.3 FH is characterized by a
significant increase in plasma low density lipoprotein cholesterol (LDL-C)
at birth.3 Clinically associated with elevated cholesterol levels, gluten-like
xanthoma, and a family history of premature coronary artery disease
(CAD), the phenotype of HoFH is much more severe than that of HeFH.4
TagedPFH is a single-gene disease that is mainly caused by low density lipo-
protein cholesterol receptor (LDLR) or apolipoprotein B (Apo B) gene
function loss mutations or proprotein convertase subtilisin/kexin-9
(PCSK9) gene function gain mutations.5 Less common causes include
gene variants encoding apolipoprotein E (Apo E) and signal transduction
adapter family member 1 (STAP1).6 LDLR is mainly localized in liver
cells, the main sites for LDL metabolism. Over 95% of FH cases are
attributed to mutations in the LDLR gene. The Apo B molecule is synthe-
sized in hepatocytes and secreted in very low-density lipoprotein
(VLDL). After the transformation of VLDL into LDL, it plays a role as
an LDLR ligand. The binding of Apo B to LDLR leads to intracellular
internalization and lysosomal degradation of LDL particles.7 Similarly,
the mutation encoded by the Apo B gene reduces LDL clearance, result-
ing in family defective apolipoprotein B-100.8 PCSK9 is a member of the
mammalian serine preprotein invertase family. It is responsible for the
proteolytic maturation of secreted proteins, including neuropeptides, hor-
mones, cytokines, growth factors, receptors, serum, and cell surface pro-
teins.9 PCSK9 can bind and degrade LDL receptors, reducing LDL
receptor clearance on serum low-density lipoprotein cholesterol (LDL-
C).10 The under diagnosis of FH in the general population is an emerging
concern. Only 1% of potentially FH patients have been detected.11 There-
fore, correct identification of the causes of dyslipidemia is very important
to inform patient management.12 For many FH patients, the primary clini-
cal manifestation is acute coronary syndrome (ACS).13 Cascade screen-
ing (family testing based on relatives of affected individuals) has
improved FH diagnosis.14 Through reverse cascade screening of children
and their parents during immunization visits, early diagnosis of young
TagedEn2 Curr Probl Cardiol, July 2023

children with FH can expand the scope of FH screening and increase the
diagnosis rate.15TagedEn
TagedPThe goal of FH treatment is to reduce the risk of atherosclerotic cardio-
vascular disease (ASCVD) and the occurrence of fatal cardiovascular dis-
ease (CVD).16 In most cases, FH treatment is initiated from childhood
through later life.17 First, before treatment, FH patients must undergo com-
prehensive therapeutic lifestyle changes18 and successively receive standard
lipid-lowering treatments (LLT), including statins and ezetimibe.19,20 Lipo-
protein apheresis (LA) therapy is a safe, effective option for FH patients
treated with the most tolerated lipid-lowering drugs. However, LDL-C con-
centrations remain higher than the target level.21TagedEn
TagedPBibliometrics analysis is a literature research method that incorporates
the literature system and bibliometric characteristics as research
objects.22 This approach23 allows for quantitative and qualitative analyses
of the literature to evaluate the research trends and show the development
frontier of the various fields.24 In addition, it compares the contributions
of different countries, institutions, journals, and scholars.25,26 Researchers
commonly employ VOSviewer and CiteSpace as bibliometric visualiza-
tion tools for data analysis and visualization.27,28TagedEn
TagedPBased on the Web of Science Core Collection (WoSCC) of Institute
for Scientific Information (ISI), we reviewed the literature on FH. VOS-
viewer and CiteSpace were used to: (i) Perform bibliometric analyses of
relevant FH-related studies published in the past 10 years; (ii) Draw
visual knowledge maps; (iii) Display the research status in the FH field;
(iv) Reveal research hotspots and development trends; and (v) Provide a
reference for future related research.TagedEn
TagedH1MethodsTagedEn
TagedH2Data CollectionTagedEn
The following search terms were used to retrieve literature from WoSCC:
Topic = (“Familial Hypercholesterolemia” OR “familial hyperlipidemia” OR
“familial dyslipidemias”). The search period was between January 1, 2011
and September 26, 2021. There were no restrictions on language or docu-
ment type. A total of 1 617 records, comprising 11 types of documents were
obtained. Notably, 834 original research papers accounted for 51.74% of
total records (Table 1). Review papers ranked second (333 reviews),
accounting for 20.47% of the total records. The other 8 document types
were conference abstracts (313 articles), editorial materials (103 articles), let-
ters (25 articles), book chapters (7 articles), online publications (6 articles),

TagedEnTABLE 1. Document types of the publications
No. Type of document TP CA SOTC ACI Proportion/% H-index

1 Article 834 13 610 24 083 28.88 51.58 66
2 Review 333 6 669 9 062 27.21 20.59 46
3 Meeting Abstract 313 60 62 0.20 19.36 3
4 Editorial Material 103 523 588 5.71 6.37 12
5 Letter 25 122 127 5.08 1.55 6
6 Book Chapter 7 144 145 20.71 0.43 4
7 Published online 6 0 0 0.00 0.37 0
8 Correction 5 0 0 0.00 0.31 0
9 News 3 1 1 0.33 0.19 1
10 Proceedings Paper 3 34 34 11.33 0.19 2
11 Reprint 1 Nm Nm Nm 0.06 Nm
TP, total publications; SOTC, sum of times cited; CA, citing articles; Nm Not mentioned; ACI,
average citations per item.
corrections (5 articles), news (3 articles), conference proceedings (3 papers),

and reprints (1 paper). A total of 33 936 times cited, 17 605 citing articles,
78 h-index, and 20.99 average per item.
TagedH2Data AnalysisTagedEn
The Microsoft Office Excel 2019, VOSviewer (v.1.6.17), and CiteSpace
(v.5.8.R2) were used to analyze all 1 617 documents. Because of its out-
standing feature of strong graphic abilities and suitability in processing
large-scale data, VOSviewer (a bibliometric software) was used to construct
relational networks and for data visualization.29 CiteSpace (a web-based
Java application) is a document visualization analysis software gradually
developed for bibliometrics analyses and data visualization. CiteSpace was
used to visually display the basic knowledge and hotspots of the FH research
field and to predict its evolutionary paths as well as research frontiers.30
Microsoft Office Excel 2019 was used to analyze temporal distributions and
to identify highly cited FH-associated studies in the past 10 years. VOS-
viewer was used to draw visual knowledge maps for distributions of: coun-
try/regions, authors, and research institutions, as well as disciplines.
CiteSpace was to evaluate the research hotspots and frontiers.
TagedH1ResultsTagedEn
TagedH2Temporal Distribution Map of the LiteratureTagedEn

The number of publications in a period reflects the research develop-
ment trends and speed of this discipline.31 Based on the number of

TagedEn TagedFiur
FIG 1. Trends in the growth of publications and the number of cited articles worldwide from
2010 to 2021 (Color version of figure is available online).TagedEn
publications in this field in the recent 10 years, research in this field is at a

stable stage, with the largest number of publications being in 2016. Com-
pared to 2019, the number of publications significantly decreased in
2020. Times cited is a crucial indicator of quantitative academic evalua-
tion. Between 2010 and 2020, the number of citations increased year after
year, with citation counts being highest for articles published in 2020
(Fig 1). In 2021, less than 10 months were counted, however, the trend
showed that the frequency of literature citations will exceed that in 2020.
TagedH2Country/Region DistributionTagedEn
As shown in Table 2, the largest number of published literatures were
from England, USA, and Australia, respectively accounting for 20.27%,
19.35%, and 11.06% of the total reports. The total number of studies
from the 3 countries accounted for more than half of the total reports,
implying that the 3 countries have a high interest in research in the FH
field. Studies from Canada (96.86), Germany (86.67), and the Nether-
lands (79.04) had the highest average citations per item (ACI), indicating
that the 3 countries started research on FH earlier, and their results are rel-
atively mature.
TagedPThe VOSviewer parameters were set as: Method (Linlog/modularity),
minimum number of documents of a country: 5. The obtained results
were from 81 countries, with 48 meeting the thresholds. Based on co-
occurrence analysis, VOSviewer classifies countries into different clus-
ters and colors them according to the time course in which they appear,

TagedEn6
TagedEnTABLE 2. Top 10 productive countries regarding the research on FH
Rank Country Region Quantity Proportion/% ACI H-index Total link strength
1 England Western Europe 328 20.27 32.99 43 492
2 USA North America 313 19.35 52.59 56 444
3 Australia Oceania 179 11.06 38.24 32 293
4 Italy Southern Europe 138 8.53 59.21 34 231
5 Netherlands Western Europe 138 8.53 79.04 44 348
6 Spain Southern Europe 121 7.48 66.99 32 282
7 Greece Southeast Europe 85 5.25 37.36 16 97
8 China East Asia 83 5.13 15.05 17 98
9 Germany Central Europe 81 5.01 86.67 24 228
10 Canada North America 78 4.82 96.86 37 179
ACI average citations per item; Here includes the automatically calculated total link strength by VOSviewer.
Curr Probl Cardiol, July 2023
TagedEn TagedFiur
TagedEnCurr Probl Cardiol, July 2023
FIG 2. Cooperation map of countries of FH (Color version of figure is available online.)TagedEn

7
superimposing time on the network of co-occurrence countries. Different
colors correspond to the year in which different countries appeared. The
more purple the color, the earlier the country appeared, and the more yel-
low the color, the later the country appeared (Fig 2) Figure 2. shows the
cooperation among countries. USA largely cooperated with France, Italy,
Japan, and the Netherlands; England closely cooperated with Germany,
Portugal, China, Canada, and Switzerland; Australia frequently cooper-
ated with Finland, Greece, Denmark, and Malaysia.TagedEn
TagedH2Distribution of Authors and Research InstitutionsTagedEn

Watts GF from the University of Western Australia was the author
with the most published articles, followed by Humphries SE from the
University of London in England and Pang J from the University of West-
ern Australia in Australia (Table 3). Three of the top ten authors were
from Australia (all from the University of Western Australia). Moreover,
2 authors were from the Netherlands.
Minimum number of documents of an author: 10. The obtained results
are for 6569 authors and 68 met the thresholds. Based on co-occurrence
analysis, VOSviewer classifies authors into different clusters and colors
them according to the time course in which they appear, superimposing
time on the network of co-occurrence authors. As shown in Figure 3A,
different clusters represent cooperation among authors. Watts GF, and
Bell DA, Bates TR, Brett T, Burnett JR, Pang J, Sullivan DR closely
cooperated. Kastelein JP worked closely with Wiegnman A, Hovingh G,
Santos RD, Hutten BA, Langslet G, and Mata P, among others.TagedEn
TagedPAs shown in Table 4, the University of Western Australia (137 papers)
was the institution that published the most research papers, followed by
Royal Perth Hospital (125 papers) and the University of London (120
papers). The Academic Medical Central Amsterdam is the research insti-
tution with the highest ACI (89.01). It is closely followed by the Univer-
sity of Amsterdam with an ACI of 81.31, and the University of S~ao Paulo
with an ACI of 80.51.TagedEn
Minimum number of documents of an institution: 16. The obtained
results were from 2 210 institutions and 36 met the thresholds. Based on
co-occurrence analysis, VOSviewer classifies institutions into different
clusters and colors them according to the time course in which they
appear, superimposing time on the network of co-occurrence institutions.
Different colors correspond to the year in which different institutions

TagedEnTABLE 3. Top 10 authors in the studies of FH
Rank Author Country Institution TP ACI H-index

1 Watts GF Australia Univ Western Australia 125 42.69 28
2 Humphries SE England Univ London 57 65.65 21
3 Pang J Australia Univ Western Australia 57 11.42 15
4 Hovingh GK Netherlands Univ Amsterdam 45 114.49 23
5 Santos RD Brazil Univ Sa~o Paulo Med Sci 43 94.58 19
6 Hegele RA Canada Univ Western Ontario 40 107.40 23
7 Bell DA Australia Univ Western Australia 36 13.83 13
8 Haralambos K Wales Cardiff Univ 35 4.26 4
9 Bourbon M Portugal Univ Lisbon 33 13.76 10
10 Kastelein JP Netherlands Univ Amsterdam 33 69.15 23
TP total publications, ACI average citations per item.
appeared. The bluer the color, the earlier the institution appeared, and the
redder the color, the later the institution appeared. As shown in
Figure 3B, the University of Western Australia, Curtin University, Fiona
Stanley Hospital, University of Melbourne, University of Sydney, Royal
Perth Hospital, and Royal Prince Alfred Hospital closely collaborated.
University of Amsterdam, McGill University, University of Palermo,
University of Pennsylvania, Sapienza University of Rome, University of
S~ao Paulo, University of Witwatersrand, Western University, Amgen Inc,
University of Cape Town, University of Helsinki and Imperial College
London, Polytechnic University of Milan closely collaborated. Oslo Uni-
versity Hospital, Universidade de Lisboa, University of Oslo, University
of Zaragoza, Hospital Clinic Barcelona, Fundacion Hypercholesterolemia
Familiar, and Hospital Universitario Miguel Servet closely collaborated.
University College London, University of Oxford, Cardiff University,
University of Teknol MARA, Imperial College London, University of
Manchester, and University of Nottingham closely collaborated.TagedEn
TagedH2Distribution of Disciplines and JournalsTagedEn

With regards to the number of published papers, Cardiovascular Sys-
tem Cardiology and Peripheral Vascular and Pharmacology Pharmacy
were the top 3 disciplines (Table 5). Additional subjects in literature
include Medicine General Internal (10.20%), Biochemistry Molecular
Biology (9.39%), Endocrinology Metabolism (8.41%), Genetics Heredity
(4.57%), Medicine Research Experimental (4.57%), Nutrition Dietetics
(3.34%), Pediatrics (3.28%), Medical Laboratory Technology (2.29%)
and other subjects.

TagedEn TagedFiur
TagedEn10
FIG 3. VOSviewer visualization map of authors and institutions in the studies of FH. (A) Cooperation map of authors. (B) Cooperation map of institutions
(Color version of figure is available online.)TagedEn
TagedEnTABLE 4. Top 10 institutions in the studies of FH
Rank Institution Country Quantity SOTC ACI H-index

1 Univ Western Australia Australia 137 5,490 40.07 28
2 Royal Perth Hosp Australia 125 3,364 26.11 27
3 Univ London England 120 6,785 56.54 29
4 UCL England 101 4,797 47.50 25
5 Univ Amsterdam Netherlands 83 6,749 81.31 36
6 Acad Med Ctr Amsterdam Netherlands 75 6,676 89.01 35
7 Imperial Coll London England 61 1,728 28.33 21
8 CIBER Spain 50 3,174 63.48 18
9 Univ Sa~o Paulo Brazil 47 3,785 80.51 19
10 Cardiff Univ Wales 46 202 4.39 6
SOTC, sum of times cited; ACI, average citations per item.
T s shown in Table 6, Atherosclerosis was the journal with the highest

agedPA
number of publications in the FH field, followed by the European Heart
Journal (68 articles), Atherosclerosis Supplements (62 articles), Journal
of Clinical Lipidology (51 articles), Circuit (44 articles) and Current
Opinion in Lipidology (38 articles). Lancet (157.61) was the journal with
the highest ACI, followed by European Heart Journal (90.74), Journal
of Lipid Research (41.52), Arteriosclerosis Thrombosis and Vascular
TagedEnTABLE 5. Top 20 subject categories in the studies of FH
Rank Quantity WoSCC Categories Percentage/%

1 615 Cardiovascular System Cardiology 38.01
2 483 Peripheral Vascular 29.85
3 177 Pharmacology Pharmacy 10.94
4 165 Medicine General Internal 10.20
5 152 Biochemistry Molecular Biology 9.39
6 136 Endocrinology Metabolism 8.41
7 74 Genetics Heredity 4.57
8 74 Medicine Research Experimental 4.57
9 54 Nutrition Dietetics 3.34
10 53 Pediatrics 3.28
11 37 Medical Laboratory Technology 2.29
12 36 Hematology 2.23
13 26 Cell Biology 1.61
14 23 Health Care Sciences Services 1.42
15 22 Multidisciplinary Sciences 1.36
16 18 Biotechnology Applied Microbiology 1.11
17 15 Toxicology 0.93
18 14 Healthy Policy Services 0.87
19 13 Neurosciences 0.80
20 13 Physiology 0.80

TagedEnTABLE 6. Top 20 journals in the studies of FH
Rank Quantity Journal ACI IF (2020) JCR

1 271 Atherosclerosis 11.62 5.162 Q2/Q1
2 68 European Heart Journal 90.74 29.983 Q1
3 62 Atherosclerosis Supplements 7.97 3.235 Q2
4 51 Journal of Clinical Lipidology 21.69 4.766 Q2
5 44 Circulation 29.690 29.69 Q1/Q1
6 38 Current Opinion in Lipidology 15.16 4.776 Q2/Q2/Q2
7 25 Journal of Lipid Research 41.52 5.922 Q1
8 23 Heart Lung and Circulation 12.22 2.975 Q3
9 20 European Journal of Preventive Cardiology 12.10 7.804 Q1
10 20 Heart 14.00 5.994 Q1
11 18 Lancet 157.61 79.323 Q1
12 15 Current Pharmaceutical Design 11.33 3.116 Q3
13 14 Current Cardiology Reports 10.07 2.931 Q3
14 14 Journal of Atherosclerosis and Thrombosis 18.36 4.928 Q1
15 13 BMJ Open 18.38 2.692 Q2
16 13 Clinica Chemica ACTA 19.00 3.786 Q1
17 13 Journal of Internal Medicine 18.77 8.989 Q1
18 13 Nutrition Metabolism and Cardiovascular Diseases 18.38 4.222 Q2/Q2/Q2
19 13 Current Atherosclerosis Reports 12.00 5.113 Q1
20 12 Arteriosclerosis Thrombosis and Vascular Biology 32.58 8.313 Q1/Q1
IF, Impact Factor; JCR, Journal Citation Reports.
Biology (32.58), Circulation (28.59), Journal of Clinical Lipidology

(21.69), and Journal of Internal Medicine (18.77).TagedEn
TagedH2Highly Cited Literatures and Co-Cited ReferencesTagedEn
TagedPHighly Cited LiteraturesTagedEn. The citation frequency of a paper is a golden

index for paper evaluation and for assessing academic quality and influ-
ence. The most frequently cited documents, also referred to as highly
cited literatures, are the focus of researchers Table 7. summarizes the top
10 highly cited literatures. The article “Familial hypercholesterolemia is
underdiagnosed and undertreated in the general population: Guidance for
clinicians to prevent coronary heart disease”3 was the most cited paper.
Nordestgaard BG et al.3 assessed the degree of preliminary FH diagnosis
and treatment and guided FH screening and treatment. The article
“Triglycerides and Cardiovascular Disease a Scientific Statement from
the American Heart Association”32 was the second most cited paper. This
paper by Miller M et al.32 reviews the critical roles of triglycerides in
lipid metabolism. The authors demonstrate that triglycerides are essential

TagedEnTABLE 7. Top 10 highly cited literatures
Rank Title Journal Type Author Year SOTC

1 Familial hypercholesterolemia is European Heart Journal Article Nordestgaard BG 2013 34 281
underdiagnosed and undertreated in
the general population: guidance for
clinicians to prevent coronary heart
disease3
2 Triglycerides and Cardiovascular Disease Circulation Article Miller M 2011 1102
a Scientific Statement from the
American Heart Association32
3 2019 ESC/EAS Guidelines for the European Heart Journal Article Mach F 2020 1009
management of dyslipidemias: lipid
modification to reduce cardiovascular
risk The Task Force for the
management of dyslipidemias of the
European Society of Cardiology (ESC)
and European Atherosclerosis Society
(EAS)5
4 Dyslipidemia in Obesity: Mechanisms and Nutrients Review Klop B 2013 555
Potential Targets98
5 Homozygous familial European Heart Journal Review Cuchel M 2014 541
hypercholesterolemia: new insights and
guidance for clinicians to improve
detection and clinical management. A
position paper from the Consensus
Panel on Familial Hypercholesterolemia
of the European Atherosclerosis
Society16
6 Article Blom D 2014 462
13
(continued on next page)

TagedEn14
TABLE 7. (continued)
Rank Title Journal Type Author Year SOTC

A 52-Week Placebo-Controlled Trial of New England Journal of
Evolocumab in Hyperlipidemia99 Medicine
7 Effect of a monoclonal antibody to Lancet Article Stein E 2012 460
PCSK9, REGN727/ SAR236553, to
reduce low-density lipoprotein
cholesterol in patients with
heterozygous familial
hypercholesterolemia on stable statin
dose with or without ezetimibe therapy:
a phase 2 randomized controlled
trial100
8 PCSK9 inhibition with evolocumab (AMG Lancet Article Raal FJ 2015 459
145) in heterozygous familial
hypercholesterolemia (RUTHERFORD-
2): a randomized, double-blind,
placebo-controlled trial101
9 Inhibition of PCSK9 with evolocumab in Lancet Article Raal FJ 2015 451
homozygous familial
hypercholesterolemia (TESLA Part B): a
randomized, double-blind, placebo-

controlled trial102
10 Efficacy and safety of a microsomal Lancet Article Cuchel M 2013 445
triglyceride transfer protein inhibitor in
patients with homozygous familial
hypercholesterolemia: a single-arm,
open-label, phase 3 study38
SOTC, sum of times cited.
biomarkers of cardiovascular disease risk. Lifestyle change is the focus
for the treatment of elevated triglyceride levels. Intensive lifestyle
changes can reduce triglyceride levels by at least 50%. The
“2019 ESC/EAS Guidelines for the Management of Dyslipidaemias:
Lipid modification to reduce cardiovascular risk by The Task Force for
the management of dyslipidaemias of the European Society of Cardiol-
ogy (ESC) and European Atherosclerosis Society (EAS)”5 was the third
most cited article. The guidelines of Mach F et al.5 regarding lipid-lower-
ing targets have been significantly updated, with the use of new lipid-low-
ering drugs and LLT programs for extremely high-risk groups, including
ACS being recommended. This version of the guidelines collectively put
forward a series of recommendations for rapid strengthening of lipid-low-
ering approached to actively manage and control secondary cardiovascu-
lar risks.5
TagedPRegarding article types, 8 of the most cited literatures are articles, while
2 are reviews. In terms of the number of citations, the guidelines have
been cited more. Judging from the publication time of highly cited litera-
tures, there were more highly cited literatures between 2011 and 2015.TagedEn
TagedPCo-Cited ReferencesTagedEn. CiteSpace parameters were set as: time slicing

(2011 2021), years per slice (1), node type (cited reference), selection
criteria (top 50 objects), and pruning (pathfinder). According to set
parameters, a network with 710 nodes, 2175 connections and 0.0086 den-
sity was obtained (Fig 4A). Modularity Q = 0.77, Silhouette S = 0.90.
Modularity is an evaluation index of network modularity. The greater the
Modularity value of a network, the better its clustering. The value space
of Q is [0,1], and Q > 0.3 indicates that the obtained network community
structure is significant.33 Silhouette is evaluated by measuring network
homogeneity. The closer the Silhouette value is to 1, the higher the net-
work homogeneity. A clustering result with a value of 0.7 is highly reli-
able. Above 0.5, clustering can be considered reasonable.33 This shows
that the network community structure in Figure 4A is credible, and the
network has a high homogeneity and high reliability. In Figure 4A, the
nodes marked with purple circles are documents with high betweenness
centrality. CiteSpace uses this indicator to measure the importance of
documents and to derive the top 10 co-cited references (Table 8). Co-cita-
tion analysis indicated that 2 references appeared in the reference list of a
third citation article, and then, the 2 references formed a co-citation
relationship.34
TagedPThe article “Familial hypercholesterolemia is underdiagnosed and
undertreated in the general population: Guidance for clinicians to prevent

TagedEn TagedFiur
TagedEn16
FIG 4. Analysis of references. (A) References co-citation network. (B) Top 20 References with the Strongest Citation Bursts (Color version of figure is available
online.)TagedEn
TagedEnTABLE 8. Top 10 co-cited references
Rank Frequency Centrality Title Journal Author Year

1 133 0.05 Familial hypercholesterolemia is underdiagnosed and European Nordestgaard 2013
undertreated in the general population: guidance for Heart BG
clinicians to prevent coronary heart disease3 Journal
2 51 0.07 Familial Hypercholesterolemia in the Danish General Journal of
Population: Prevalence, Coronary Artery Disease, and Clinical
Cholesterol-Lowering Medication103
Endocrinology & Metabolism Benn M 2012
3 49 0.04 Homozygous familial hypercholesterolemia: new insights and European Cuchel M 2014
guidance for clinicians to improve detection and clinical Heart
management. A position paper from the Consensus Panel on Journal
Familial Hypercholesterolemia of the European
Atherosclerosis Society16
4 44 0.02 2016 ESC/EAS Guidelines for the Management of European Catapano AL 2016
Dyslipidemias The Task Force for the Management of Heart
Dyslipidemias of the European Society of Cardiology (ESC) Journal
and European Atherosclerosis Society (EAS) Developed with
the special contribution of the European Association for
Cardiovascular Prevention & Rehabilitation (EACPR)85
5 42 0.04 Use of low-density lipoprotein cholesterol gene score to Lancet Talmud PJ 2013
distinguish patients with polygenic and monogenic familial
hypercholesterolemia: a case-control study104
6 40 0.05 Familial hypercholesterolemia in children and adolescents: European Wiegman A 2015
gaining decades of life by optimizing detection and Heart
treatment105 Journal
7 39 0.20 Efficacy and Safety of Alirocumab in Reducing Lipids and New England Robinson JG 2015
Cardiovascular Events37 Journal of
Medicine
17
(continued on next page)

TagedEn18
TABLE 8. (continued)
Rank Frequency Centrality Title Journal Author Year

8 38 0.02 Diagnostic Yield and Clinical Utility of Sequencing Familial Journal of the Khera AV 2016
Hypercholesterolemia Genes in Patients with Severe American
Hypercholesterolemia106 College of
Cardiology
9 34 0.10 Efficacy and safety of a microsomal triglyceride transfer protein Lancet Cuchel M 2013
inhibitor in patients with homozygous familial
hypercholesterolemia: a single-arm, open-label, phase 3
study38
10 32 0.03 ESC/EAS Guidelines for the management of dyslipidemias: European Reiner Z 2011
the Task Force for the management of dyslipidemias of the Heart
European Society of Cardiology (ESC) and the European Journal
Atherosclerosis Society (EAS)107
coronary heart disease”3 was the most cited while “Familial Hypercholes-
terolemia in the Danish General Population: Prevalence, Coronary Artery
Disease, and Cholesterol-Lowering Medication”35 was the second most
cited. In their paper, Marianne B et al.35 suggested that in a general popu-
lation of white Danish individuals, the prevalence of FH is higher than
commonly perceived, with at least half of the affected subjects not receiv-
ing cholesterol-lowering medication. Irrespective of the use of medica-
tions, the very high risk of CAD reflects the extent of under diagnosis and
under treatment of FH in the community and primary care.35 The
“Homozygous familial hypercholesterolemia: New insights and guidance
for clinicians to improve detection and clinical management. A position
paper from the Consensus Panel on Familial Hypercholesterolemia of the
European Atherosclerosis Society”16 was the third most cited article. The
consensus panel on familial hypercholesterolemia of the European Ath-
erosclerosis Society (EAS)16 conducted a rigorous review of the existing
HoFH data, emphasizing the need for early identification of HoFH
patients, timely referral to specialized centers, and early initiation of
appropriate treatment.16TagedEn
TagedPIn CiteSpace, nodes with more than 0.1 mediation centrality become the
key points.36 In Table 8, the betweenness centrality of “Efficacy and Safety
of Alirocumab in Reducing Lipids and Cardiovascular Events.”37 was 0.2.
Jennifer G et al.37 conducted a randomized trial involving 2341 high-risk
cardiovascular patients with LDL-C levels 70 mg/dl who received the
maximum tolerated dose of statins for treatment. They found that in 78
weeks, when alirocumab was added to statin therapy at the maximum toler-
ated dose, LDL-C levels were significantly reduced. In post-event analysis,
alirocumab was shown to reduce incidences of cardiovascular events.37 The
betweenness centrality of “Efficacy and safety of a microsomal triglyceride
transfer protein inhibitor in patients with homozygous familial hypercholes-
terolemia: A single-arm, open-label, phase 3 study.”38 was 0.1. The study38
reports that the benefit risk ratio of lomitapide is favorable for HoFH
patients. When young, these patients have a higher risk of cardiovascular
events and death. Therefore, lomitapide may be a valuable drug in HoFH
treatment.38 In Tables 7 and 8, these 3 documents3,5,38 are not the only liter-
atures with highly cited literatures, but also co-cited references.TagedEn
TagedPFigure 4B presents the top 20 references with the strongest citation
bursts. The strongest citation burst was for the 2015 article3 “Familial
hypercholesterolemia is underdiagnosed and undertreated in the general
population: Guidance for clinicians to prevent coronary heart disease:
Consensus Statement of the European Atherosclerosis Society.” This arti-
cle has an intensity of 30.52.TagedEn

TagedH2Research Hotspots and Frontier AnalysisTagedEn
TagedPResearch Hotspots AnalysisTagedEn. Keywords are the core and essence of a

paper. Analysis of high-frequency keywords reflects the hotspots in a par-
ticular research field. We used key co-occurrence analysis to determine
the main directions and hotspots in FH research as well as to uncover the
development and changes of its theme structure.39 Combine synonyms to
get Table 9. As shown in Table 9, along with diseases, including familial
hypercholesterolemia, cardiovascular disease, hyperlipidaemia, athero-
sclerosis, and heterozygous familial hypercholesterolemia. The more fre-
quent keywords were risk, cholesterol, density-lipoprotein cholesterol,
and diagnosis among others.
TagedPThe VOSviewer parameters were: Method (Linlog/modularity), Mini-
mum number of occurrences of a keyword: 20. There were 4 272 key-
words, and 125 keywords met the thresholds. For each of the 125
keywords, the total strength of co-occurrence links with other keywords
was calculated. Keywords with the greatest total link strength were
selected. The keyword co-occurrence network graph (Fig 5) shows that
the thicker the connection between nodes, the higher the frequency of 2
keywords appearing together. Keywords formed 4 clusters, representing
the 4 main research directions in the FH field.TagedEn
TagedPThe red cluster is associated with FH complications. The specific associ-
ated diseases were atherosclerosis, hypertension, ischemic heart diseases,
obesity, stroke, and type-2 diabetes mellitus. Inflammatory factors, risk fac-
tors, and underlying mechanisms included CRP, inflammation, insulin
resistance, intima-media thickness, metabolism, and oxidative stress.TagedEn
TagedPThe green cluster mainly focuses on FH diagnosis, consisting of diag-
nosis, mutations, genetic causes, genetic testing, phenotype, LDLR, lipid
levels, and cost-effectiveness.TagedEn
TagedPThe blue cluster focuses on treatment with the new lipid-lowering drugs,
including alirocumab, evolocumab (AMG 145), lompitade, mipomersen,
PCSK9 inhibitors, triglyceride transfer protein, monoclonal antibody, dou-
ble-blind, RCT, Apo B, efficiency, safety, inhibition, LLT, LA, and other
keywords. Current evidence shows that 3 new lipid-lowering drugs, includ-
ing microsomal TG transfer protein inhibitors, Apo B 100 synthesis inhibi-
tors, and PCSK9 inhibitors have been approved for clinical use.TagedEn
TagedPThe yellow cluster focuses on statin therapy as the main research direc-
tion with the following keywords: adolescents, children, young adults,
statin therapy, statins (HMG-CoA reductase), atorvastatin, ezetimibe,
rosuvastatin, follow-up, and primary prevention.TagedEn

TagedEnTABLE 9. Top 20 keywords in the studies of FH
Rank Keywords Occurrences Total link strength Rank Keywords Occurrences Total link strength
1 Familial hypercholesterolemia 680 3 732 11 Prevalence 103 656
2 Cardiovascular disease 588 6 371 12 PCSK9 97 677
3 Hyperlipidemia 334 1 859 13 Children 97 603
4 Risk 243 1 531 14 LDL cholesterol 94 669
5 Cholesterol 209 1 234 15 Heterozygous familial hypercholesterolemia 93 705
6 Atherosclerosis 192 1 111 16 Efficacy 90 706
7 Density-lipoprotein cholesterol 163 1 166 17 Double-blind 90 698
8 Diagnosis 150 975 18 Stain therapy 90 683
9 Low-density-lipoprotein 120 662 19 Guidelines 77 581
10 Management 118 822 20 Monoclonal antibody 76 600
Here includes the automatically calculated total link strength by VOSviewer.
21
TagedEn TagedFiur
TagedEn22
FIG 5. Map of keyword clustering in the studies of FH (Color version of figure is available online.)TagedEn
TagedEn TagedFiur
FIG 6. Top 15 keywords with the strongest citation bursts (Color version of figure is available online.)TagedEn
TagedPResearch Frontiers IdentificationTagedEn. Based on the keywords co-occurrence

network, we conducted the keywords emergent word detection. The top 15
keywords with the strongest citation bursts in the FH research field within
the past 10 years are reported. As shown in Figure 6, the blue line denotes
the time axis while the red segment on the blue time axis shows the burst
detection, indicating the start year, end year, and burst duration. Notably,
reducing lipid had the strongest citation bursts, followed by general popula-
tion, care, triglyceride transfer protein, insulin resistance, cost effectiveness,
apolipoprotein b, AMG 145, receptor, cardiovascular risk factor, gene, pla-
cebo-controlled trial, metabolic syndrome, LDL, and simvastatin. Based on
start time of emergence, it is shown that in the past 10 years, insulin resis-
tance, apolipoprotein B, receiver, cardiovascular risk factor, gene, meta-
bolic syndrome, LDL, and simvastatin appeared early, and were the
subjects of early attention. Care is the current research frontier in FH, and
is already in an explosive period.
TagedH1DiscussionTagedEn
TagedH2General InformationTagedEn
Given the number of FH publications, research on FH is at a stable
stage. The number of publications in 2016 was the largest, and this could

have been because since 2015, medical and scientific communities have
increased their awareness of FH-associated burden.40 During this period,
the European Medicines Agency and the US Food and Drug Administra-
tion approved 2 monoclonal antibodies, PCSK9 inhibitors, aliroucomab
and evolocomab, for lowering LDL-C to treat FH, especially HoFH.41 It
is vital to systematically evaluate the scale of new drugs, treatment dura-
tion and efficacy, drug price and care cost in the target population.42 The
significant decrease in publications in 2020 compared to 2019 may be
due to a shift in scientific focus across countries towards the onset of the
Corona Virus Disease 2019 (COVID-19) pandemic at the end of 2019.
The times cited of FH-related literatures is increasing year by year,
implying that focus on this field is stable.
TagedPResearch on FH began in developed countries, indicating that FH-
related research in these countries is relatively mature. For instance,
many high-quality studies on FH have been conducted by the University
of Western Australia and the Royal Perth Hospital in Australia, as well as
the University of London in England. In terms of the number of national
studies, England has the most relevant studies. Notably, China is among
the top 10 Asian countries with the highest number of studies on FH.
These data show that FH research has gradually received attention in
Asian countries. The abundance of these studies in developed countries
compared to low - and middle-income countries43 may be due to gene
testing-associated costs, which are prohibitive for low-income coun-
tries.40 Although gene testing is not a universal method, it is the “gold
standard” for FH diagnosis.16 It is indicated that FH cases account for
nearly 1% of global estimated reports (based on available data), with
most of them (80%) being from Western countries, which is in tandem
with our findings.11 Most of the cooperation among institutions is within
country. Cooperation among European countries is relatively close, how-
ever, cooperation among other countries is low. Among the research insti-
tutions, the Academic Medical Central Amsterdam had the highest ACI.
Apart from the University of S~ao Paulo Medical Science in Brazil, other
regions have fewer contacts between agencies. Therefore, it is imperative
to strengthen international cooperation, eliminate academic barriers, and
promote FH research development.TagedEn
TagedPProfessor Watts GF of the University of Western Australia has pub-
lished the most articles and has the highest h-index on FH-related
research. H-index is an important indicator of a researchers’ scientific
output.44 Professor Watts GF has published many high-quality articles on
FH in the following research institutions: School of Medicine, Faculty of
Health and Medical Sciences, University of Western Australia, Perth,

Western Australia, Australia, and Lipid Disorders Clinic, Department of
Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia.
These 2 research institutions have conducted the most research on FH,
with the University of London in England in third place. The above
authors and institutions have a high academic reputation in the field of
FH, and have made important contributions towards the progress and
development of the FH field.TagedEn
TagedPWe believe that the exchanges on FH within disciplines are extensive.
Advances in these related disciplines will be important in future research
development in this field. The top 20 journals on FH studies are mostly in
Q1 or Q2. These findings indicate that the above-mentioned journals
have a strong academic performance with regards to FH research. Among
the most cited journals, Lancet (IF79.323, Q1), European Heart Journal
(IF29.983, Q1) and Circulation (IF 29.690, Q1) have impact factors (IF)
values higher than 29. IF were obtained by querying Journal Citation
Reports (JCR) 2020. This shows that the 3 journals have published high-
quality research with convincing and mature results.TagedEn
TagedPThe top 10 cited literatures focus on new lipid-lowering drugs (PCSK9
inhibitors), especially evolocumab; the management of dyslipidemia in
FH patients and guidelines for CVD risk, as well as on phase 2 or phase 3
clinical studies involving HoFH patients. The top 10 co-cited references
mainly focused on the management of FH patients, gene sequencing of
FH patients, and clinical studies of alirocumab, a PCSK9 inhibitor, etc.
Therefore, blood lipid level management among FH patients, clinical tri-
als, and related studies on PCSK9 inhibitors are the focus of current
research. Meanwhile, the importance of guidelines in guiding clinical and
scientific research work is illustrated. Literatures with the most cited
times and most co-citation frequencies play a very important role in the
FH field. It is worth noting that citations do not fully reflect the quality of
an article, as earlier published articles generally have higher citations
than more recent ones.45TagedEn
TagedH2The Hotspots and FrontiersTagedEn

Based on cluster analysis of keywords and timeline viewer, the current
research hotspots on FH are mainly categorized into 4 aspects: the mech-
anisms of FH and associated complications, FH diagnosis, statin therapy,
and new lipid-lowering drugs. Of particular importance is the new lipid-
lowering drug (PCSK9 inhibitor). Currently, care is in an explosive
period, and will become a hot frontier in the FH field.

TagedPMechanisms of FH and Its ComplicationsTagedEn. According to the keywords,
the red cluster involves the mechanisms of FH and its complications. We
combined the keywords with the relevant literature for analysis. Long-
term exposures to high LDL-C levels have been associated with an
increased risk of ASCVD.46 Compared to the non-FH population, the
young FH population has the highest risk of CVD.47 FH is a potential risk
factor for peripheral vascular and ischemic cerebrovascular diseases. The
increase in intima-media thickness is associated with future CHD and
stroke events.48,49 Moreover, intima-media thickness is an intermediate
phenotype of CVD risk in FH subjects. Kusters DM. et al.50 found early
atherosclerosis in HeFH children. Moreover, carotid artery intima-media
thickness in these children was increased, compared to unaffected sib-
lings. Hypertension is a common risk factor for CHD. Through neurohu-
moral action, hypertension increases FH-associated atherosclerosis by
activating angiotensin II, norepinephrine, and cytokines.51,52 Obesity,
especially visceral obesity, is associated with insulin resistance. Accom-
panied by compensatory hyperinsulinemia, insulin resistance increases
the risk of type 2 diabetes, hypertension, dyslipidemia, CHD, and pro-
motes atherosclerosis development.53,54 Oxidative stress represents an
imbalance between oxidative and antioxidant defense systems. In most
cases, oxidative stress is accompanied by chronic inflammation, espe-
cially in the pathogenesis of atherosclerosis, metabolic disorders, and
cancer. Clinically, FH is characterized by severe high cholesterol levels,
manifesting as imbalances of systemic oxidative stress.55,56 Through spe-
cific literature interpretation of these involved keywords, FH-related
mechanisms and complications can be understood.
TagedPThe Diagnosis of FHTagedEn. The second cluster is mainly associated with FH

diagnosis. The analysis was based on the involved keywords. The clinical
definition of FH is based on 1 of 3 standards, which adopts genetic testing
to varying degrees.57 The American make early diagnosis prevent early
death (MEDPED) standards based on measured TC and LDL-C levels.58
The Simon-Broome standard recommends LDL-C measurements in cases
of combined patients with xanthoma, first- or second-degree relatives, or
functional gene mutations.59 The Dutch DLCN criteria are scored accord-
ing to family history, measured LDL-C, clinical history, and genetic test-
ing. Notably, genetic testing recommends all possible diagnoses and
diagnoses of all first-degree relatives of a diagnosed case.60 It can provide
a diagnostic certainty in many cases and reduce the burden of undiag-
nosed FH.61 The genotype-phenotype relationship of patients with FH-
related mutations is highly heterogeneous. Most FH patients carry

pathogenic variants in the LDLR coding region, PCSK9 and Apo B,
mainly LDLR loss-of-function mutations. Loss of LDLR functions is
associated with decreased protein expressions, impaired LDL-C clear-
ance, and excess LDL in circulation.17 Mutations in genes encoding
ATP-binding cassette subfamily G members 5 and 8 (ABCG5 and
ABCG8) may cause FH.62 64 Laurens et al.65 reported that nearly 2.4%
of FH patients had (possibly) pathogenic heterozygous variants at the
ABCG5 and ABCG8 sites. Carriers of these mutations have lower levels
of LDL-C, when compared to FH patients with LDLR mutations. These
genes may (partly) explain the FH phenotype of some individuals, though
they may cause the inherited pattern of autosomal dominant hypercholes-
terolemia in the FH family. The combination of statins with ezetimibe
forms the basis for FH treatment, which is cheap and effective. However,
due to elevated LDL-C levels among FH patients, often, this combination
does not sufficiently achieve treatment goals, even with maximum doses.
Therefore, PCSK9 inhibitors and MTP inhibitors, among others, provide
new strategies for patients to meet treatment goals. However, cost-associ-
ated implications of these drugs limit their use.66,67 Cost-associated
implications of PCSK9 inhibitors for HeFH or ASCVD treatment and
their potential impacts on USA health care expenditures have been
reported.68
TagedPStatin TherapyTagedEn. The yellow cluster mainly involves stain therapy. We

conducted specific analysis based on the involved keywords. LDL-C is
the main treatment target that guides primary and secondary prevention
of atherosclerosis.69,70 In a primary prevention cohort study, Martin BM
et al.71 found that, compared to patients aged 20-69, elevated LDL-C lev-
els in patients aged 70-100 was associated with a significantly increased
absolute risk of myocardial infarctions and ASCVD. Statins are the main
lipid-lowering drugs for FH patients. High-dose high-efficiency drugs are
the first choice. Although randomized trials of statins have not been
reported in the FH population, observational studies indicate a reduced
mortality rate.72,73 A study by Simon BR et al.74 in England found that
the prognosis of HeFH patients has significantly improved, and the coro-
nary artery mortality rate has been reduced by about one-third since the
introduction and widespread use of statins. In this view, strict clinical fol-
low-up is required for FH patients as they have an increased risk of pre-
mature CVD.
TagedPNew Lipid-lowering DrugsTagedEn. The blue cluster mainly involves new lipid-
lowering drugs. Three new lipid-lowering drugs, including microsomal

triglyceride transfer protein (MTP) inhibitors, Apo B100 synthesis inhibi-
tors, and PCSK9 inhibitors, have been approved for clinical use.
TagedPLompitade, an MTP inhibitor, has no associations with LDLR activi-
ties and is effective in most HoFH cases.75 MTP is expressed in hepato-
cytes and in intestinal cells. MTP mediates triglyceride transfer to Apo B
particles to form VLDL and chylomicrons.76 Lomitapide has a high inci-
dence of adverse reactions, mainly manifested as elevated transaminase,
fatty liver, and gastrointestinal adverse reactions. Therefore, there is a
need to evaluate the effectiveness and safety of the drug.77,78,79TagedEn
TagedPMipomersen, an Apo B100 synthesis inhibitor, is a second-generation
antisense oligonucleotide. Mipomersen suppresses the production and
secretion of VLDL and reduces LDL-C by targeting antisense oligonu-
cleotides of the Apo B100 messenger ribonucleic acid
transcription.80,81,82 Studies have reported significantly reduced levels of
atherosclerotic lipoproteins (LDL-C, Apo B, and Lp (a)) following the
addition of mipomersen to lipid-lowering therapy, which may provide
patients with new treatment options.83 The most frequent adverse reac-
tions of mipomersen are injection site reactions, including local rash,
swelling, itching, and pain. However, most of the adverse reactions are
mild to moderate.84TagedEn
TagedPMonoclonal antibodies that target PCSK9 have been approved for FH
treatment to supplement traditional LLT.85 Incorporation of anti-PCSK9
antibodies to standard treatments with statin monotherapy or statin com-
bined with ezetimibe can reduce serum LDL-C levels by about 60% and
significantly reduce CVD incidences, compared to placebo.86 PCSK9
promotes LDLR binding and degradation, thereby reducing LDLR-driven
clearance of serum LDL-C.87 Elevated PCSK9 levels are associated with
hypercholesterolemia. The gain of function mutations in the PCSK9 gene
is one of the reasons for the aggravation of FH and CVD.88,89 PCSK9
monoclonal antibodies include alirocumab and evolocumab.90 Subcuta-
neous injections of alirocumab and evolocumab every 2 or 4 weeks can
reduce LDL-C by 50%-60%,91 and reduce cardiovascular events.92,93TagedEn
TagedPCurrently, Care Is the Frontier of Research in This Field, And It Is

Currently in An Explosive PhaseTagedEn. Care is the main keyword in current
studies; therefore, we postulate that care is the frontier of research in the
FH field. FH is a genetic disease; comprehensive care (medicine treat-
ment, lifestyle intervention, skincare, psychological care, and personal-
ized discharge guidance among others) can improve its clinical
outcomes. There is a need to provide special diagnosis and management
centers for FH patients. Moreover, the government should guarantee the

care of severe HoFH patients and develop a family-based care plan that
ensures patients get an opportunity to participate and share decisions
throughout the life cycle. By integrating primary and specialty care, fam-
ily member screening, genetic counseling, social support, community
health workers, and the development of specific resources, this care
model will ensure that FH patients receive the best services.17
TagedPBalla S et al.94 reviewed the care of women with FH, emphasizing on
gender differences in FH treatment. Throughout their life, women with
FH are impacted differently. For instance, they choose contraceptives
from teenage years, the LLT, the timing of pregnancy, the choice of
breastfeeding or resumption of treatment, and finally, determine the goal
of menopausal care. Balla S et al.94 reported that early detection and
appropriate treatment before interrupting fertility treatment can signifi-
cantly reduce morbidity and mortality. Access to health care differs
between men and women. Increasing awareness of this disease may
improve the diagnosis rates. Martin et al.95 reported that the best care for
children and adolescents with FH requires a multidisciplinary framework
that integrates primary care, pediatric specialists, and adult services.
Wald DS et al.96 documented that it is feasible and effective to screen
child parent family hypercholesterolemia in primary care practices at
routine child immunization visits while Patel P et al.97 demonstrated that
there was statistical significance between patients diagnosed with FH and
adverse cardiovascular outcomes and higher nursing costs. Therefore, it
may become a research hotspot in the future.TagedEn
TagedH2LimitationsTagedEn
This study has some limitations. First, the analysis of this study is
based on articles from the WoSCC database, which is the most well-
known database of scientific publications on many research topics, how-
ever, other databases such as PubMed, Scopus may provide a broader
coverage. Second, CiteSpace and VOSviewer cannot completely replace
system retrieval. For instance, the obtained documents are from 2011 to
2021. However, with continuous updating of WoSCC documents, the
number of obtained studies are different from the actual number of docu-
ments, and citations as well as h-index will accordingly change. Third,
we included all literatures on FH in the WoSCC database, however, due
to differences in quality among the studies, credibility of the analysis
may be low. Visual analysis based on literatures lays a foundation for
understanding the research topics, research hotspots and development
trends in in the field of FH.

TagedH1ConclusionTagedEn
Through information visualization technology, we elucidated on the
research progress, research hotspots, and research frontier in the FH field
in the past 10 years. The findings inform investigations on FH and iden-
tify the potential partners for interested researchers. Research on FH is at
a stable stage and the cited times has been increasing year after year.
Compared to the developing countries, more FH research has been con-
ducted in developed countries. It is necessary to strengthen international
cooperation and exchanges. We have identified the scholars, institutions,
relevant journals, and representative literatures that play an important
role in this field. The research direction of FH is on the mechanisms of
FH and its complications, diagnosis of FH, statin therapy, and new lipid-
lowering drug therapy. Notably, the new lipid-lowering drug PCSK9
inhibitor is prominent. Care is currently the frontier of research in this
field, and it is currently in an explosive period.
TagedH1SummaryTagedEn
The manuscript summarizes the latest progress, hotspots as well as
frontiers, future research development trends and references in this field.
TagedH1Authors ContributionTagedEn
Namin Wei and Guoxiu Liu designed the study. Siyu Li, Guozhen
Yuan, and Xintian Shou collected the data. Xuesong Zhang re-examined
the data. Namin Wei, Guoxiu Liu, and Jingjing Shi analyzed the data.
Namin Wei wrote the manuscript. Yuanhui Hu and Huaqiang Zhai
reviewed and revised the manuscript. All authors contributed to the arti-
cle, approved the submitted version, and agree to be held responsible for
all aspects of the work.
TagedH1FundingTagedEn
The manuscript did not receive any specific grant from funding agen-
cies in the public, commercial, or not-for-profit sectors.
TagedH1AcknowledgmentsTagedEn
The authors acknowledge Home for Researchers editorial team (www.
home-for researchers.com) for language editing service.

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Namin Wei is a PhD student at Beijing University of Chinese Medicine, her main research direction
is the basic and clinical research of atherosclerosis.
Yuanhui Hu, MD, doctoral tutor, has been engaged in basic and clinical research of cardiovascular
diseases in Guang’anmen Hospital, China Academy of Chinese Medical Sciences for more than
30 years.
Guoxiu Liu is a PhD student at Beijing University of Chinese Medicine, her main research direction
is Chinese Medical Standardization.
Siyu Li is a PhD student at Beijing University of Chinese Medicine, her main research direction is
Chinese Medical Standardization.
Guozhen Yuan is PhD student in Guang’anmen Hospital, China Academy of Chinese Medical Scien-
ces, her main research direction is the basic and clinical research of cardiovascular diseases.
Xintian Shou is a PhD student in Guang’anmen Hospital, China Academy of Chinese Medical Scien-
ces, his main research direction is the basic and clinical research of cardiovascular diseases.
Xuesong Zhang is a PhD student in Guang’anmen Hospital, China Academy of Chinese Medical
Sciences, her main research direction is the basic and clinical research of cardiovascular diseases.
Jingjing Shi, MD, works in Guang’anmen Hospital, China Academy of Chinese Medical Sciences,
mainly engaged in basic and clinical research of cardiovascular for 8 years.
Huaqiang Zhai, MD, doctoral tutor, works in Beijing University of Chinese Medicine for more than
20 years. His main research direction is the prevention and treatment of respiratory diseases with Chi-
nese medicine, and is very interested in the basic and clinical research of cardiovascular diseases.

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T Bibliometric Analysis of Familial

TagedPAbstract: Familial Hypercholesterolemia (FH), an

TagedEnCurr Probl Cardiol, July 2023 1

TagedEn2 Curr Probl Cardiol, July 2023

TagedEnCurr Probl Cardiol, July 2023 3

No. Type of document TP CA SOTC ACI Proportion/% H-index

corrections (5 articles), news (3 articles), conference proceedings (3 papers),

TagedH2Temporal Distribution Map of the LiteratureTagedEn

TagedEn4 Curr Probl Cardiol, July 2023

publications in this field in the recent 10 years, research in this field is at a

TagedEnCurr Probl Cardiol, July 2023 5

TagedEnTABLE 2. Top 10 productive countries regarding the research on FH

FIG 2. Cooperation map of countries of FH (Color version of ﬁgure is available online.)TagedEn

TagedH2Distribution of Authors and Research InstitutionsTagedEn

TagedEn8 Curr Probl Cardiol, July 2023

Rank Author Country Institution TP ACI H-index

TagedH2Distribution of Disciplines and JournalsTagedEn

TagedEnCurr Probl Cardiol, July 2023 9

Rank Institution Country Quantity SOTC ACI H-index

T s shown in Table 6, Atherosclerosis was the journal with the highest

TagedEnTABLE 5. Top 20 subject categories in the studies of FH

Rank Quantity WoSCC Categories Percentage/%

TagedEnCurr Probl Cardiol, July 2023 11

Rank Quantity Journal ACI IF (2020) JCR

Biology (32.58), Circulation (28.59), Journal of Clinical Lipidology

TagedH2Highly Cited Literatures and Co-Cited ReferencesTagedEn

TagedPHighly Cited LiteraturesTagedEn. The citation frequency of a paper is a golden

TagedEn12 Curr Probl Cardiol, July 2023

TagedEnTABLE 7. Top 10 highly cited literatures

Rank Title Journal Type Author Year SOTC

(continued on next page)

Rank Title Journal Type Author Year SOTC

randomized, double-blind, placebo-

TagedPCo-Cited ReferencesTagedEn. CiteSpace parameters were set as: time slicing

TagedEnCurr Probl Cardiol, July 2023 15

TagedEnTABLE 8. Top 10 co-cited references

Rank Frequency Centrality Title Journal Author Year

(continued on next page)

Rank Frequency Centrality Title Journal Author Year

TagedEnCurr Probl Cardiol, July 2023 19

TagedPResearch Hotspots AnalysisTagedEn. Keywords are the core and essence of a

TagedEn20 Curr Probl Cardiol, July 2023

TagedEnTABLE 9. Top 20 keywords in the studies of FH

TagedPResearch Frontiers IdentificationTagedEn. Based on the keywords co-occurrence

TagedEnCurr Probl Cardiol, July 2023 23

TagedEn24 Curr Probl Cardiol, July 2023

TagedH2The Hotspots and FrontiersTagedEn

TagedEnCurr Probl Cardiol, July 2023 25

TagedPThe Diagnosis of FHTagedEn. The second cluster is mainly associated with FH

TagedEn26 Curr Probl Cardiol, July 2023

TagedPStatin TherapyTagedEn. The yellow cluster mainly involves stain therapy. We

TagedEnCurr Probl Cardiol, July 2023 27

TagedPCurrently, Care Is the Frontier of Research in This Field, And It Is

TagedEn28 Curr Probl Cardiol, July 2023

TagedEnCurr Probl Cardiol, July 2023 29

TagedEn30 Curr Probl Cardiol, July 2023

TagedEnCurr Probl Cardiol, July 2023 31