Epidemiology of familial hypercholesterolaemia: Community and clinical

Atherosclerosis 277 (2018) 289e297

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Review article

Epidemiology of familial hypercholesterolaemia: Community and clinical Antonio J. Vallejo-Vaz*, Kausik K. Ray Imperial Centre for Cardiovascular Disease Prevention (ICCP), Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom

a r t i c l e i n f o

a b s t r a c t

Article history: Received 15 April 2018 Received in revised form 6 June 2018 Accepted 14 June 2018

Familial hypercholesterolaemia (FH) is a genetic disorder affecting the metabolism of low-density lipoprotein (LDL) particles, leading to high LDL-cholesterol levels maintained over time and higher risk of cardiovascular disease (CVD) early in life. Contemporary studies have challenged prior estimations of FH prevalence and suggest this condition to be more frequent than previously considered, with an overall prevalence rate of 1:200e300 individuals in the general population (1:160,000e300,000 for homozygous FH). However, prevalence of FH varies around the world. In part this is due to an artefact of approaches of detection and methods used to diagnose FH (e.g. lack of gold standard for diagnosis of FH, different criteria applied, availability of genetic testing). But also due to intrinsic characteristic of different populations, e.g. higher presence of founder effects or rates of consanguinity. Additionally, results from many regions are lacking and it is estimated that only a small percentage of subjects with FH would have been diagnosed overall. FH entails a significantly higher risk of CVD, reported to be higher than that estimated by conventional risk assessment tools for the general population. This risk is mainly driven by coronary heart disease. Despite this evidence, low rates of patients meet therapeutic targets for cardiovascular prevention, and implementation of therapy (high intensity statins, combination therapy) is needed. The introduction of novel lipid-lowering therapies may improve this situation. In the present review, we discuss the epidemiology of FH overall, with special attention to different aspects related to prevalence, cardiovascular risk and prognosis, and treatment of FH. © 2018 Elsevier B.V. All rights reserved.

Keywords: Familial hypercholesterolaemia Primary dyslipidemia LDL cholesterol Epidemiology

1. Introduction Since C. Muller first reported, in 1938, the clustering of xanthomas, high blood cholesterol and myocardial infarction [1] (MI) and years later (1970s) Brown and Goldstein described the genetic defects in the low-density lipoprotein (LDL) receptor (LDLR) as the cause of familial hypercholesterolaemia (FH) [2], our understanding of this condition has grown considerably. The subsequent introduction of statins substantially improved the prognosis of the disease [3,4]. And the recent development of novel therapies such as pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has raised expectations with regards to achieving therapeutic goals

* Corresponding author. Department of Primary Care and Public Health, School of Public Health, Imperial College London; Charing Cross campus, W6 8RP, London, United Kingdom. E-mail address: [email protected] (A.J. Vallejo-Vaz). https://doi.org/10.1016/j.atherosclerosis.2018.06.855 0021-9150/© 2018 Elsevier B.V. All rights reserved.

and further reductions of adverse outcomes associated with FH [5,6]. FH is a genetic disorder with an autosomal dominant inheritance affecting LDL-cholesterol (LDL-C) metabolism resulting in reduced catabolism of LDL particles, high levels of LDL-C and premature cardiovascular disease (CVD) [7,8]. Mutations in the LDLR gene are the most frequent cause of FH (85e90% of cases) [9,10]. Although a few mutations are responsible for most FH cases in regions with founder effects, a wide range of mutations have been described, and currently >1700 mutations in the LDLR have been reported worldwide [11]. Both heterozygous FH (HeFH) and homozygous FH (HoFH, resulting from the same mutation in the same gene [true homozygous] or, more often, compound heterozygous mutations whereby there are mutations at different sites in the same gene) have been described [7,8]. Additionally, mutations in the apolipoprotein B (apoB)-100 gene (which is the ligand for the LDLR, whereby mutations in the protein may prevent/alter the binding of LDL particles to its receptor) or mutations in the PCSK9

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gene (gain-of-action mutations leading to increased lysosomal LDLR degradation) can cause FH with an indistinguishable phenotype to that produced by mutations in LDLR [9,10]. Additionally there are the so-called double heterozygotes where individuals carry mutations in different genes (e.g. LDLR and apoB). Occasionally mutations in other genes have also been described resembling the classical FH phenotype, leading to forms of autosomal dominant hypercholesterolaemia (e.g. mutations in gene STAP1 [signal transducing adaptor family member 1]) [12]; or the rare autosomal recessive loss-of-function mutation in gene LDLRAP (LDLR adaptor protein 1) [13]. Finally, in a variable percentage of patients no mutations are identified [14], suggesting that other genes/type of mutations (others than those tested in a particular setting) could be involved or that a polygenic basis results in higher LDL-C in these subjects [7]. New evidence on the epidemiology of FH from large studies and from different regions have been accumulating during the last few years; a renewed interest in this condition has emerged, partly related to the recognition of a likely higher frequency of the disease than previously considered, and partly due to the development of new lipid-lowering medications (LLM) that could improve the management of FH. Notably, data has emerged from outside of Europe demonstrating that FH is a global public health issue. In the present review we aim to present a general overview, with a focus on the most recent data available, of some epidemiological aspects of FH prevalence, cardiovascular risk and prognosis, and patterns of treatment and goals achievement in FH. Other topics will be more extensively covered in other articles of the present FH series. For the present review we carried out a search in Medline to identify relevant papers on the topic, including “familial hypercholesterolaemia”, “primary hyperlipidaemia”, “prevalence” and related terms, not restricted to a particular time frame (though we focus on more recent data, as most of the global evidence has accrued since 2011). 2. FH prevalence Prevalence of HeFH has been traditionally considered to be ~1:500 individuals in most ethnic groups throughout the world [7]. However, in most cases, these figures result from the extrapolation, e.g. by using the Hardy-Weinberg equation, of a limited number of data from selected populations or specific subgroups to the general population, and therefore may lack the precision of more contemporary estimates [15]. For instance, the prevalence of HeFH in Denmark was suggested to be ~1:950 individuals from data from late 1970s [15], but recent analyses from the large communitybased Copenhagen General Population Study (CGPS) in unselected individuals revealed that HeFH could be as frequent as ~1:200 subjects [16,17]. In fact, overall contemporary data suggests HeFH to be much more frequent and affect ~1:200e300 individuals globally [7,16,18], which could mean that >30 million individuals worldwide could be affected of HeFH [7]. HoFH is, on the contrary, much less frequent than HeFH, from 1:1,000,000 people, based on historical prevalence data, to 1:160,000e300,000, as suggested from recent studies [8]. Additionally, the prevalence of the disease seems to vary with ethnicity and geographically, with higher prevalence reported in subpopulations with founder effects/communities sharing ascendants or in those with higher rates of consanguinity (e.g. Afrikaners in South Africa, Christian Lebanese, Tunisians, some FrenchCanadian) [15,19,20]. Furthermore, a number of other factors complicate reliable estimation of the true prevalence of FH in the general population, e.g.: lack of large, standardised and comparable national registries; variability in clinical practice; lack of uniform criteria for the diagnosis of FH, limited availability of genetic tests,

discordance between individuals identified by clinical and genetic diagnosis, the potential for mutations not yet known and the case of “polygenic” hypercholesterolaemia; differences in screening strategies and initiatives to identify FH patients and relatives, lack of resource provision, and concerns about their feasibility and costeffectiveness; lack of FH awareness and education among healthcare professionals, other healthcare providers and policy-makers; misclassification of case fatalities to alternate causes [21,22]. 2.1. FH diagnosis Presently, it is estimated that as few as <5% of individuals affected by HeFH have been identified in most regions so far, with the only exception being a few countries where there have been active screening programmes [7]. Even so, in these better performing countries the under-diagnosis is still patent when one considers the contemporary prevalence data [7]. A key point which arbitrarily influences estimations of prevalence is how this condition is defined and the classification used to estimate the likelihood of having a diagnosis of FH. For example, the use of different LDL-C cut-off points or the inclusion or not of genetic mutation criteria may vary substantially the number of cases identified and classified as FH [23]. The identification of new FH subjects is currently mainly based on clinical criteria and, where available and indicated, genetic testing [7,24,25]. However, currently there is no “gold standard” for the diagnosis of FH, with the presence of a positive mutation being widely acknowledged to define a definite diagnosis, though it has to be confirmed that such a mutation is pathogenic, i.e. affecting the LDL metabolism leading to increased LDL-C levels. On the other hand, however, a FH mutation is not found in a significant proportion of patients with a clinical diagnosis of FH, suggesting presence of unknown mutations, that in a number of cases a “polygenic” basis may account for this hypercholesterolaemic phenotype, or the potential for misclassification of some individuals as having FH (false positives) [23,26]. Widely accepted diagnostic criteria to identify FH phenotype include the Dutch Lipid Clinic Network (DLCN) criteria, SimonBroome criteria, and MEDPED (Make Early Diagnosis to Prevent Early Deaths) [7,10,24,25]. The first two contain a number of variables including DNA analysis, LDL-C levels, physical signs related to hypercholesterolaemia, clinical history of premature CVD and family history, and classifies individuals into definite/probable/ possible/unlike FH, in case of DLCN, or definite/possible in case of Simon-Broome criteria. On the contrary, MEDPED is based only on LDL-C levels according to age [10]. These diagnostic criteria were produced some time ago and from Western populations; to what extent they fit well to changes in contemporary populations and to populations from other regions and ethnicities is an area of considerable uncertainty; for instance, lower average cholesterol levels have been described in Asian populations [27,28], which may lead to potential under-diagnosis of FH (false negative) if the same LDL-C cut-off points are used as suggested in some diagnostic criteria. Recently new algorithms have been developed trying to adapt these to other populations or simplify the diagnosis; this is the case of the new criteria proposed for the Japanese population [29] or that proposed by the American Heart Association [30]. Another point to consider is the limited availability of genetic testing in many regions and the associated costs limiting their widespread implementation [21]. A frequent problem when trying to estimate the prevalence from general population epidemiological studies is that these studies frequently lack information on some criteria (e.g. physical signs, family history …) which are intrinsic to these classifications and a better fit for an outpatient referral clinic but unlikely to be applicable in a large general purpose population study. Thus, full

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algorithms cannot often be applied but modifications are used instead. Finally, it is worth mentioning the current debate on the extent to which high levels of lipoprotein(a) may contribute to the clinical diagnosis of FH (which may confound the population prevalence figures of FH), based on the recent findings from Langsted et al. [31] These authors found that in subjects with clinical FH, lipoprotein(a) levels were around 40e60% higher than those classified as unlikely to have FH. The authors suggest that cholesterol in lipoprotein(a) contributes to the overestimation of LDL-C levels in some patients with a clinical diagnosis of FH; this suggests that a proportion of patients might obtain a clinical diagnosis of FH based on high lipoprotein(a) concentrations. The authors suggest that variations in the LPA gene leading to high lipoprotein(a) levels might be a possible “cause” of clinical FH [31]. This term seems to be misleading as what data are implying is clinical misclassification. In support of a lack of causality is the data from the SAFEHEART study in molecularly-defined FH patients which suggest that LDLR defects would be partly responsible for the observed increase in lipoprotein(a) in these patients [32]. Further discussions on FH diagnosis and screening strategies are covered specifically in other articles of the present FH series. 2.2. FH prevalence in the general population A recent (2017) systematic review assessing the prevalence of HeFH included a total of 21 studies from Europe (9 studies), North America (4), Australia (3), Asia (2), South Africa (1), or pooled from international cohorts (2 studies) [18]; this work, though, exposes the challenges to making precise estimates due to the variability in the methods used to assess FH, with different criteria used to diagnose FH (DLCN criteria, genetic sequencing, LDL-C measurements only, Simon-Broome criteria, MEDPED criteria). In this contemporary review the estimated prevalence in individual studies ranged

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from 0.05% to 5.62%. A meta-analysis of 19 of these studies yielded an overall FH prevalence in the general population of 0.40% (1:250 individuals, 95% confidence interval [CI]: 1:192 to 1:345) [18]; however, a substantial between-study heterogeneity was observed (I2 ¼ 99.3%), supporting the variability of the studies (design, population, methods, FH diagnosis …) and regional variations. Taken together, it is perhaps inappropriate without standardization and systematic approaches to generate an overall figure to apply to all populations. An overview of HeFH prevalence in the general population from contemporary studies is shown in Fig. 1. Europe. The first large study aiming to directly estimate the prevalence of FH in unselected general population was published in 2012 and carried out in Denmark using the CGPS, a communitybased population including >69,000 individuals [16]. Using a modified DLCN definition (e.g. to account for the lack of information on xanthomas, arcus corneal or some family history data), the prevalence of definite/probable FH combined was estimated to be as high as ~1:137 participants (0.73%) (definite FH eDLCN score >8 pointse 0.20% [1:504]; probable FH eDLCN 6e8 pointse 0.53% [1:189]). However, it was observed that this prevalence varied substantially depending on the diagnostic classifications used; for instance, applying the MEDPED criteria led to an estimated prevalence of 0.80% (1:128) for probable FH, whereas using the SimonBroome criteria yielded a prevalence of definite or possible FH of 4.1% (1:25) [16]. A later study (2016) from the same authors on the same population-based study, including now >98,000 participants, genotyping for LDLR and apoB variants accounting for almost 40% of pathogenic FH mutations in Copenhagen, suggested an overall prevalence of known FH-causing mutations of 0.46% (1:217) [17]. This latter prevalence is higher than that reported from the National FINRISK and Health 2000 Studies in Finland by genotyping 5 common LDLR founder mutations in this country (estimated to account for 78% of FH cases in Finland) in >28,500 individuals; this

Fig. 1. Overview (non-systematic review) of overall prevalence rates reported from contemporary studies for heterozygous familial hypercholesterolaemia in the general population (without [unknown] founder effects). See text for further details and explanations. Modified diagnostic criteria where frequently applied (see main text). Map created from https://mapchart.net/. CI: confidence interval; DLCN: Dutch Lipid Clinic Network; FH: familial hypercholesterolaemia; MEDPED: Make Early Diagnosis to Prevent Early Deaths; Ref: reference.

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study estimated the overall prevalence of FH in Finland to be at least 0.17% (at least 1:600 individuals) [33]. Other recent data published in Europe broadly agree with the aforementioned estimated prevalence range, though the results are not always consistent, likely suggesting cross-regional/ country differences (apart from potential variations in study designs or FH definitions). For instance, a meta-analysis of 6 population-based studies in Poland including almost 38,900 individuals suggested a prevalence of potential FH (definite and probable FH according to DLCN criteria) of 1:247 (0.41%, 95%CI 0.28%e0.53%), with FH being more prevalent in women than men and with highest prevalence figures in age groups 45e54 years in men (0.33%) and 55e64 years in women (0.77%) [34]. In Spain, an overall prevalence of FH of 1:300 has been suggested [35] (estimated to affect at least 100,000 people in Spain [36]), and 1:319 people have been estimated to have FH in the Netherlands [37], whereas in Germany, a figure of 1:278, based on DLCN criteria (definite/probable FH), or 1:295, based on MEDPED criteria, have been recently reported [38]. In primary care setting in Italy, a prevalence of 0.19% (1:526) for FH with a DLCN score 6 was found [39], whereas figures based on LDL-C levels only yielded a prevalence of 1:1038 (~0.1%) among non-treated subjects and 1:369 (~0.3%) among statin-treated patients when using the cut-off of 250 mg/dL (1:34 and 1:29, respectively, if cutoff used is  190 mg/dL) [40]. Middle East. Retrospective screening of a large regional healthcare database comprising 685,314 insured individuals <75 years in Israel found a prevalence of probable FH of 1:355 based on MEDPED criteria, with FH being more prevalent in certain communities (e.g. Israeli Druze, Christian Arabs) due to founder effects and higher rates of consanguinity [41]. In Christian Lebanese, due to similar reasons, an estimated prevalence of 1:85 was previously reported [15]. The prevalence of FH in other Middle Eastern countries is not well known, though a high frequency is expected in some regions and communities due to higher rates of shared ascendants, consanguinity and ethnic minorities [42]. Americas. In North America, the National Health and Nutrition Examination Survey (NHANES) 1999e2012 (derived from general populations) have been used to estimate the frequency of FH and extrapolate it to the overall US adult population [43]; applying a restricted DLCN score (information on some criteria was not collected in NHANES, including genetic testing) suggests that the overall US prevalence of probable/definite FH is estimated to be 0.40% (1:250, 95%CI 1:311 to 1:209), similar in men and women, suggesting that ~834,500 US adults may have probable or definite FH; of interest, the prevalence varied with race/ethnicity, e.g. 0.40% (1:249) in whites, 0.47% (1:211) in blacks, or 0.24% (1:414) in Mexican Americans [43]. A significantly higher frequency of FH has been observed in FrenchCanadians in certain regions in the province of Quebec in Canada, ranging from 1:167 up to 1:81, which is explained by the presence of a genetic founder effect [20]. Information on the prevalence of FH in Latin-American countries is generally lacking [44,45]; some reports have cited an LDL-C >190 mg/dL to be present in 11.2% of adults in Mexico and 5% in Brazil [44], and a preliminary report from a systematic FH detection program in Argentina suggests that as many as 1:152 individuals might have FH according to DLCN criteria [46]. Asia. Asian countries have been described to have, in general, lower levels of cholesterol compared to Western countries, which may have favoured an under-diagnosis in these regions [27,28]. However, mean total cholesterol levels have been increasing in some Asian regions in the last few decades, particularly east and southeast Asia, including China and Japan, partly due to changes in lifestyles [47]. As a result of more systematic assessment of

cholesterol levels FH may be more prevalent than previously envisaged in these populations. Though there is a growing interest of this condition in Asia, data to infer true estimates of the frequency of FH are broadly lacking and in some cases discordant. An early report from Japan in 1977 reported a frequency of FH of 0.11% out of 2700 consecutive outpatients attending their clinics (~1:900) using an alternative, more restrictive, definition of FH [48], which contrasts with a more contemporary (2011) estimation of the prevalence in the same district in Japan of 1:208 [49]. A recent report from China in 2014, applying a modified definition of DLCN to adapt it to the Chinese population, estimated a prevalence of probable/definite FH of 0.28%, yielding an age-standardised FH prevalence in China of 0.31% based on the 2000 Chinese census data [50]. Pacific region. Watts et al. have described a prevalence of definite/probable FH (modified DLCN definition) of 1:353 (0.28%, 95% CI 0.16%e0.41%) in a large unselected population-wide study across Australia including almost 11,000 adults [51]. In another cohort, comprising >7300 individuals who volunteered for a risk assessment for CVD and clinical trials, the corresponding prevalence was 1:229 (0.44%, 95% CI 0.26%e0.62%) [51]. Africa. The prevalence of FH in Africa is largely unknown. FH frequency has been described to be amongst the highest in the world in some communities in South Africa; in fact, it has been reported to affect ~1% of Afrikaners, Jews and Indians in South Africa (estimated prevalence between 1:70 to 1:100), likely due to the presence of founder effects, at least in the first two populations [15,52]. An estimated frequency of 1:165 for HeFH in Central and Southern Tunisia has been reported based on data on HoFH in this region [53].

2.3. Homozygous FH HoFH is a rare disorder but life-threatening [8]. Individuals affected use to have very high LDL-C, usually >500 mg/dL, and develop overt atherosclerotic CVD (ASCVD) early in life, often in the adolescence and not surviving past 30 years if left untreated [8]. Estimates based on historical data suggested that HoFH affected ~1 in one million people [8], except for higher frequencies in populations where a founder effect exists (e.g. French-Canadians, Afrikaners in South Africa, Christian Lebanese) [8,15,19]. However, as with the case of HeFH, this overall prevalence has been questioned by more recent studies, which suggest its frequency to be much higher than previously anticipated, in the range of 1:160,000 from some estimations in Denmark to 1:300,000 people [8]. For instance, Sjouke et al. found a prevalence of molecularly-defined HoFH of ~1:300,000 after screening >104,600 individuals in the Netherlands (~1:400,000 for homozygous/compound heterozygous for LDLR mutation carriers; over 1:4,180,000 for homozygous apoB mutation carriers) [37]. Of interest, these and other authors have found the clinical phenotype of HoFH to be more variable than that described previously with only around half of these HoFH subjects meeting the classical HoFH diagnosis criteria with LDL-C >500 mg/dL, and not necessarily restricted to very young individuals [37,54,55]. In Spain 97 genetic HoFH patients were identified from a total of 16,751 genetic studies for FH diagnosis performed between 1996 and 2015; these data applied to the mean Spanish population for the same period yielded an estimated prevalence of genetically diagnosed HoFH of 1:450,000 [55]. In Germany, however, a lower prevalence of ~1:860,000 has been estimated [56]. In the Hokuriku district in Japan a prevalence of 1:171,167 was reported in 2011 [49]. In all these studies, the majority of HoFH cases were true homozygotes or compound heterozygotes for the LDLR.

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2.4. FH in children Overall, it has been suggested that 20%e25% of FH patients around the world would be children and adolescents [57]. Assuming an overall prevalence of 1:250, based on reported rates of ~258 worldwide births per minute, it would mean that ~1 child with FH is born per minute worldwide [57,58]. An LDL-C >190 mg/ dL in children, or >160 mg/dL if having a relative with high LDL-C or premature CHD, suggests a high probability for the child to have a genetically-based FH [57]. Since the potential influence of dietary and hormonal factors are limited during childhood compared to older ages, this period has been suggested to be optimal to identify FH individuals and discriminate them from non-FH subjects [57], specially within the interval of 1e9 years of age [59]. However, the initiatives to identify subjects with FH at this early stage of life are scarce. In Slovenia, a national universal screening programme for hypercholesterolaemia in 5-year-old children has been implemented during the last few decades [59]; simulated detection rates of FH from this programme has been estimated to be >96% in the last years considering an incidence of 1:500; however, if an FH incidence of 1:200 is assumed only ~38% of the at-risk population would have been detected [59]. Information on the frequency of the diagnosis and detection rates of FH in children is broadly lacking. Secondary analyses from NHANES in US adolescents 12e19 years of age defining FH as an LDL-C >190 mg/dL (no information on personal and family history of early ASCVD and high cholesterol collected in NHANES participants of these ages) estimated a FH prevalence ranging from 0.42% (1:237; 95%CI 0.15%e0.70%) (similar to that estimated for US adult population) to 0.17% (1:583; 95%CI 0.06%e0.28%) with a more conservative approach [43]. In 217 children and adolescents 8e18 years old (median 15 years) with a molecular confirmation of FH included in the SAFEHEART cohort in Spain, numbers of FH males and females were similar, a history of ASCVD was not present in any of them (but over 16% had history of premature familial ASCVD) and only 1 had xanthomas [60]. Nevertheless, these characteristics could vary significantly among different world regions, based, for example, on awareness of FH by physicians and rates of suspicion and early detection. 3. FH and cardiovascular risk and prognosis Individuals with FH are exposed to elevated LDL-C levels since birth. The exposure to this lifelong burden of LDL-C and its accumulation results in the development of atherosclerotic lesions early in live [7,8,57]. The burden of atherosclerosis and the likelihood of CVD is both “dose”-related and cumulative and can be considered the product of LDL-C levels and duration of exposure [61]. In support of this is the observation that those with the highest LDL-C levels require the shortest exposure before there is clinical manifestation of CVD; for instance, in cases of HoFH, most patients develop overt atherosclerosis before the age of 20 years, and generally do not survive past 30 years if remained untreated [8]. Similarly, individuals with HeFH also have a significantly higher risk of CHD [9,25,50]. This risk is especially high in those <40 years old [62], with much higher rates of CHD mortality in both sexes compared to the general population [4]. Hence, HeFH entails a significantly greater risk of CHD, estimated to be at least 30% higher in women by the age of 60 years and as high as 50% in men by the age of 50 compared to those without HeFH [9,25,63]. Thus FH accelerates the natural atherosclerosis process due to ageing in a time and dose-dependent fashion. In addition, importantly, it has been observed that for any LDL-C level considered, the risk of CHD is significantly higher among FH mutation carriers than non-carriers [23]. As such, Khera et al. found that in patients with an LDL-C

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>190 mg/dL (compared to subjects with an LDL-C <130 mg/dL), those carrying a FH mutation had a 22-fold higher risk of CHD, whereas this risk was limited to 6-fold higher among patients without a mutation [23]. ASCVD risk in FH patients is mainly driven by CHD, whereas the risk posed by FH in stroke is more controversial. Analysis from Denmark in >100,000 individuals found no significant difference in the cumulative incidence of stroke (unless the participants already suffered from ischemic heart disease) between those with and without FH causative mutations (4% and 7%, respectively, developed ischemic stroke, p ¼ 0.5) unlike the results for MI (20% and 8% had MI, respectively, p < 0.001) [64]. Data from the SAFEHEART registry in molecularly-defined HeFH patients (compared with unaffected relatives as controls) have shown results in the same direction, with significant differences in the frequency of history of CHD in FH but no differences with controls in cerebrovascular events [65]. In this study, peripheral artery disease was also more frequent in patients with FH compared with controls. As expected, based on the aforementioned comments, the prevalence of FH among patients with CHD is elevated and it suggests that the CHD population, in particular when the disease is premature, should be subjected to screening for FH. For instance, the EUROSPIRE IV study found that as much as 1 in 5 patients with MI under the age of 50 years in Europe had potential FH (defined as definite/probable FH emodified DLCN criteria), though the agestandardised prevalence of potential FH varied substantially among countries [66]. In the same direction a study in Switzerland including >4700 patients hospitalized for acute coronary syndrome (ACS) found that 1.6% had probable/definite FH and 18% possible FH according to DLCN criteria, whereas the Simon-Broome criteria identified 5.4% of patients having possible FH [67]. Importantly, these figures significantly increased among young patients having premature ACS; in these cases the prevalence significantly raised to 4.8% and 47% for probable/definite and possible FH, respectively, with DLCN, and 14.0% for possible FH with Simon-Broom criteria. The prevalence of genetically-confirmed FH in patients with ACS aged 65 years in a study in Spain has been recently reported to be 8.7% (95% CI 4.3%e16.4%) [68]. Finally, a recent study among patients referred to cardiac rehabilitation and prevention centres in Italy due to stable CHD or after an ACS found that overall ~4.2% of them had potential FH according to DLCN criteria, but again this prevalence substantially increased to 10% among men <55 years/women <60 years of age [69]. Of interest, in this study a similar overall prevalence of potential FH was found among those patients who were referred due to lower extremity peripheral arterial disease. Individuals with FH have a future cardiovascular risk that is considered to exceed that of the general population, meaning that conventional risk prediction tools may underestimate this risk when applied to individuals with FH. In support of this notion, a recent analysis of a clinical trial in men aged 45e64 years in primary prevention found that among those with primary elevations of LDL-C >190 mg/dL (i.e. at least possible FH according to DLCN criteria) the observed cardiovascular risk was twice the one predicted at baseline by a risk score (Fig. 2) [70]. Recently there have been attempts to establish criteria aiming to assess and stratify the risk of CVD specifically in FH patients. For instance, a consensus panel from the International Atherosclerosis Society proposed in 2016 a definition of severe FH based on a number of criteria including LDL-C levels, high-risk factors and presence of subclinical and clinical atherosclerotic disease [71]. Other authors have proposed a score based on 5 clinical variables to predict prevalent CVD in patients with HeHF (Montreal-FH-Score) [72]. Recently, a risk prediction equation of incident atherosclerotic CVD has been proposed from the SAFEHEART longitudinal study [73]. Age, male sex, history of previous ASCVD, high blood pressure, increased body

Network of FH specialists/lipid clinics, referral specialist centres Media and general misinformation Cultural factors …. FH: familial hypercholesterolaemia.

Media and general misinformation Cultural factors ….

Patients' organisations

Availability of therapies (e.g. more potent statins, ezetimibe, PCSK9 inhibitors, apheresis) Perception of side effects Type of practice setting e.g. procedure vs. prevention, resources e.g. nurse specialists Cultural factors ….

Data available on FH in the specific region/country National/large registries Resources Specific detection programmes and initiatives (universal, cascade, opportunistic) Reimbursement programmes for screening and therapy Degree of suspicion Diagnostic criteria adapted to the specific population Availability of genetic testing Therapy implementation

“System”-related factors

FH education and awareness, general and by policy-makers Health policies and health systems FH education, awareness and knowledge Adherence to guidelines and recommendations. Variability in clinical practice

Early detection and initiation of lipid-lowering treatment has resulted in significant improvements in outcomes in patients with FH [7], and prognosis appears to be directly related to achieved LDL-C levels [76]. In HeFH, a decline in rates of cardiovascular events has been observed since the introduction of statins. For instance, in the UK Simon-Broome Familial Hyperlipidaemia Register, a reduction in the risk of CHD and all-cause mortality among 20-79-year-olds with HeFH was observed when comparing the periods before 1992 and thereafter until 2006 [77]. Furthermore, as shown in a cohort study by Versmissen et al., early initiation of therapy in HeFH patients is associated with a lower (almost 80%) risk of CHD compared to “untreated” (delay in starting statin therapy) patients, leading to almost similar rates of MI to that age-matched subjects from the general population [3]. However, even in those on statins, studies suggests that the risk of CVD still remains high as consequence of an insufficient therapy or a delay in starting therapy [7]. In many cases FH patients will generally need intensive LLM, often including combined LLM treatment, to “normalize” LDL-C levels [7].

Physician-related factors

4. FH and treatment

Table 1 Potential factors influencing familial hypercholesterolaemia diagnosis, management and goals achievement.

Fig. 2. Observed versus predicted risk of cardiovascular events in primary prevention patients with primary elevations of LDL-cholesterol above 190 mg/dL in the WOSCOPS trial. Male patients without evidence of vascular disease at baseline, without diabetes, with primary elevation of LDL-C above 190 mg/dL and an estimated 10-year predicted risk of cardiovascular events of less than 7.5% according to the Pooled Cohort Risk Equation. In the WOSCOPS trial, however, the risk observed for these patients (placebo-controlled arm) was already 7.5% at 5 years [70].

mass index, smoking, and LDL-C and lipoprotein(a) levels were found to be independent predictors of incident CVD and used to develop this equation. The equation performed well to discriminate FH patients who experienced an event during the follow-up (mean 5.5 years) in this molecularly-defined FH cohort. Thus, though this SAFEHEART risk equation requires external validation in other different cohorts, these results suggest it might represent a useful tool to estimate incident CVD risk in patients with FH in daily practice [73]. A variable that has risen a particular interest in FH in last years is lipoprotein(a), since it has been observed that its levels are often higher in patients with FH and may predict CVD risk independent of LDL-C [31,74]; Some studies have shown that among FH patients cardiovascular risk is considerably lower among those with lipoprotein(a) < 50 mg/dL [31,74]. Conversely FH patients with elevated lipoprotein(a) may benefit from even greater reductions in LDL-C as few therapies materially reduce lipoprotein(a) [75].

FH education and awareness Identification of affected relatives. Presence of founder effects Accessibility to health care and resources Compliance Side effects of treatment Costs of treatment

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Available data suggest that, in general, FH is undertreated in those already diagnosed with FH (either not treated, insufficiently treated or treatment introduced too late) [3,7,16,78,79]. For instance, in the CGPS only 48% of subjects with FH were on statin [16]. In a cross-sectional study in The Netherlands only 21% of FH patients achieved an LDL-C goal of <2.5 mmol/L, despite nearly all of them (96%) being on statins; among those not at target, 73% were not on combination therapy of maximum statin dose and ezetimibe [80]. Recent cross-sectional analysis from the CASCADE-FH registry in US showed that only 42% of patients were on high-intensity statin therapy and less than half (45%) were taking more than one LLM; in terms of goal attainments, among patients receiving LLM only 25% achieved an LDL-C <100 mg/dL (or 41% achieved a reduction of at least 50% in LDL-C levels) [79]. In the SAFEHEART study, despite a significant improvement in the use of LLM (increase use of statins and doses, combination therapy with ezetimibe) during the follow-up, still relevant low rates of FH patients achieved recommended LDL-C goals [78]. The recent introduction of therapy with novel PCSK9 inhibitors may positively impact and change this situation, since these drugs, usually on top of statins, have shown in clinical trials to produce greater reductions of LDL-C levels and higher rates of LDL-C goal achievements in FH patients [5,6]. Factors which influence control of LDL-C levels are likely multifactorial and are summarized in Table 1. These include patient-related factors, physician-related factors and societal factors, to name a few. 5. Conclusions The prevalence of FH varies around the world and this is part an artefact of approaches to detection, methods used to diagnose FH and founder effects. Broadly, the prevalence estimated from contemporary studies seems to be about twice as common as previously perceived, and it results in premature morbidity and mortality. Globally ~90e95% of patients affected by FH are thought to be undetected. Future work to identify cases earlier and institute effective treatment should result in significant benefits in public health globally. Conflicts of interest AJ Vallejo-Vaz reports honoraria for a lecture from Amgen and non-financial support from Regeneron, outside of the submitted work. KK Ray reports grants from Sanofi, Regeneron, Amgen, Pfizer, and MSD, and personal fees from Medicines Company, Sanofi, Amgen, Regeneron, Pfizer, Kowa, Algorithm, IONIS, Esperion, Novo Nordisk, Takeda, Boehringer Ingelheim, Resverlogix, Abbvie, Cerenis, Cipla, Mylan, Janssen, and Lilly, outside the submitted work. Authors contributions The present review article was conceived by KKR and AJVV. AJVV wrote the draft of the present paper. Both authors critically reviewed the manuscript and approved its submission. References [1] Muller C. Xanthomata, hypercholesterolemia, angina pectoris, Acta Med. Scand. 95 (S89) (1938) 75e84. [2] M.S. Brown, J.L. Goldstein, A receptor-mediated pathway for cholesterol homeostasis, Science 232 (4746) (1986) 34e47. [3] J. Versmissen, D.M. Oosterveer, M. Yazdanpanah, J.C. Defesche, D.C. Basart, A.H. Liem, J. Heeringa, J.C. Witteman, P.J. Lansberg, J.J. Kastelein, E.J. Sijbrands, Efficacy of statins in familial hypercholesterolaemia: a long term cohort study,

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