Coronary Heart Disease, Peripheral Arterial Disease, and Stroke in Familial HypercholesterolaemiaHighlights
Insights From the SAFEHEART Registry (Spanish Familial Hypercholesterolaemia Cohort Study)
Objective—Heterozygous familial hypercholesterolemia (FH) is the most common premature atherosclerotic cardiovascular disease (ASCVD)–related monogenic disorder, and it is associated with ischemic heart disease. There is limited information whether FH increases the risk of peripheral arterial and cerebrovascular disease. Our aim was to analyze ASCVD prevalence and characteristics in different arterial territories in a large FH population, to compare them with an unaffected control population and to determine which factors are associated to ASCVD.
Approach and Results—SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) is an ongoing registry of molecularly defined patients with heterozygous FH in Spain. ASCVD in the different arterial territories was analyzed, as well as individual characteristics, genetic variables, and lipid-lowering therapies. The study recruited 4132 subjects (3745 ≥18 years); 2,752 of those enrolled were molecularly diagnosed FH cases. Median age was 44.0 years (45.9% men) and 40 years (46.6% men) in FH patients and unaffected relatives (P<0.001). ASCVD was present in 358 (13.0%) and 47 (4.7%) FH patients and unaffected relatives, respectively (P<0.001). History of premature ASCVD was more prevalent in FH patients (9.4% and 2.4% in FH patients and unaffected relatives, respectively; P<0.001). Coronary artery–related manifestations and peripheral artery disease were more prevalent in FH patients than in controls, but no significant differences were found for cerebrovascular events. Age, body mass index, type 2 diabetes mellitus, high blood pressure, previous use of tobacco, and lipoprotein(a) >50 mg/dL were independently associated with ASCVD.
Conclusions—The prevalence of ASCVD is higher, and the involvement of the arterial territories is different in FH patients when compared with their unaffected relatives. Age, male sex, increased body mass index, hypertension, type 2 diabetes mellitus, smoking habit, and lipoprotein(a) >50 mg/dL were independently associated to ASCVD.
Heterozygous familial hypercholesterolemia (FH) is a genetic disorder characterized by autosomal inheritance in genes related to LDL receptor (LDLR) and mutations in other genes, which results in lifelong elevation of LDL-cholesterol (LDL-C).1 The major clinical manifestation of FH results from the prolonged exposure of the vasculature to high levels of LDL-C, which leads to the development of atherosclerotic lesions.2–4 It is the most common premature atherosclerotic cardiovascular disease (ASCVD)–related monogenic disorder, being life expectancy shortened by 20 to 30 years when compared with unaffected subjects.5 Although the type of mutation is probably the most influent variable in the clinical expression of ASCVD in FH, there are other genetic, environmental, and metabolic risk factors that might play a significant role in modulating the atherosclerotic burden in these individuals but the interaction among these risk factors and LDL-C levels in both FH subjects and their unaffected relatives is not well understood.6–8 Published estimates of the magnitude of ASCVD risk are highly variable. Furthermore, many reports on this topic were conducted before the introduction of statins as a standard treatment.
FH is associated with premature ischemic heart disease, but there is limited information whether FH increases the risk for peripheral arterial and cerebrovascular disease.4 This scarce information makes difficult to establish and develop health policies to decrease the disease burden that this genetic disorder provides. The SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) was designed to improve the knowledge about the prognostic factors and mechanisms that influence the development of ASCVD and mortality in a FH population.9
The aim of this work was to analyze ASCVD prevalence, manifestations, and characteristics in different arterial territories in a large FH population, to compare them with an unaffected control population and to determine which factors are associated to ASCVD in FH patients.
Materials and Methods
Materials and Methods are available in the online-only Data Supplement.
Four thousands one hundred and thirty-two subjects were enrolled. Of the total population, 3745 were ≥18 years. Of them, 2752 were FH cases (Figure 1). Median age was 44.0 (34.0–57.0) and 40 (29.0–53.0) years in FH patients and unaffected relatives, respectively (P<0.001). At enrollment, 1264 FH patients (45.9%) and 463 unaffected relatives (46.6%) were men (P=0.7).
Clinical history of ASCVD was present in 358 (13.0%) and 47 (4.7%) FH patients and unaffected relatives, respectively (P<0.001). Median age of onset of clinical cardiovascular events was 48.0 years (38.0–57.0) in FH patients and 55.0 years (48.0–61.0) in unaffected relatives (P=0.001). Among FH subjects, median age of onset of clinical cardiovascular events was 45.5 years (37.8–53.3) in male patients and 52.0 (41.0–64.8) in female patients (P<0.001). In FH patients, mean age of onset of clinical cardiovascular events was 46.45±10.78 years in male patients and 52.04±14.30 in female patients (P<0.001), and in unaffected relatives, mean age of onset of clinical cardiovascular events was 52.5±11.05 years in male patients and 60.36±6.97 in female patients (P=0.03). Main characteristics for FH patients and unaffected relatives are shown in Table 1. Median age at inclusion was significantly higher in FH patients than in unaffected relatives (44.0 versus 40.0 years in FH patients and unaffected relatives, respectively; P<0.001). History of premature ASCVD was more prevalent in FH patients (9.4% and 2.4% in FH patients and unaffected relatives, respectively; P<0.001). Nevertheless, there were no statistically significant differences in the history of premature familial ASCVD (22.4% and 20.7% in FH patients and unaffected relatives, respectively; P=0.28). Active smoking was more prevalent in unaffected relatives than in FH patients (26.4% and 33.9% in FH patients and unaffected relatives, respectively; P<0.001). Total cholesterol, LDL-C, non–high-density lipoprotein cholesterol, APOB and lipoprotein(a) (Lp(a)) were significantly higher in FH patients than in unaffected relatives. High-density lipoprotein cholesterol and triglycerides were significantly higher in unaffected relatives.
FH Patients’ Characteristics Depending on the Presence of Previous ASCVD
Table 2 shows the main characteristics and their differences between FH patients with and without ASCVD. A statistically significant higher prevalence of male sex, history of premature familial ASCVD, type 2 diabetes mellitus (T2DM), hypertension, corneal arcus, and xanthomas was found among FH patients with ASCVD. On the contrary, a statistically significant lower prevalence of active tobacco smoking was seen in those FH subjects with ASCVD. Age, body mass index, triglycerides, and Lp(a) levels were higher in FH patients with ASCVD. Two thousands two hundred and fourteen FH patients (80.45%) and 236 unaffected relatives (22.76%) were on lipid-lowering therapy (LLT) at enrolment. Total cholesterol, LDL-C, high-density lipoprotein cholesterol, non–high-density lipoprotein cholesterol cholesterol, and Apo B were significantly higher in FH patients without ASCVD.
Functional Mutations and LLT
We identified 209 different functional mutations in LDLR and APOB genes. Distribution and types of mutations are depicted in Tables 1 and 2. No significant differences in the type of mutations were found between FH patients with and without previous ASCVD (Table 2).
The use of different high-intensity LLT regimens is shown in Table 2. A significantly higher prevalence of use of ezetimibe, maximum combined therapy, and maximum LLT was found among FH patients with ASCVD when compared with FH patients without ASCVD.
Atherosclerotic Cardiovascular Disease
Main ASCVD manifestations are shown in Table 3. The estimated risk of ASCVD among patients with FH was estimated as follows: odds ratio (OR) 3.01 (2.20–4.12) for FH patients compared with patients who do not have FH. Every coronary artery–related manifestation was statistically significant higher in FH patients than in controls. The same significance was found for peripheral artery disease. Nevertheless, no significant differences were found for those events related to the cerebrovascular system. Figure 2 shows the relative distribution of cardiovascular territories clinically involved in FH patients and their unaffected relatives.
Multivariable analysis showed that age (OR, 1.07; 95% confidence interval [CI], 1.06–1.09), body mass index (OR, 1.05; 95% CI, 1.02–1.09), T2DM (OR, 1.58; 95% CI, 0.95–2.61), high blood pressure (OR, 1.83; 95% CI, 1.27–2.63), previous use of tobacco (OR, 2.50; 95% CI, 1.82–3.44), and Lp(a) >50 mg/dL (OR, 2.14; 95% CI, 1.57–2.92) were independently associated with the presence of ASCVD in FH patients. Furthermore, female sex (OR, 0.27; 95% CI, 0.20–0.38) was an independent protective factor. Interestingly, familial history of premature ASCVD and the type of mutation (null or defective) were not independently associated to the existence of ASCVD.
This study shows the high prevalence of ASCVD in FH subjects (13.0%), which is 3-fold higher than in unaffected relatives, although in this control population, the cardiovascular factors burden, except for LDL-C, was significantly higher. To our knowledge, this is the largest work describing the prevalence and location and the variables associated to ASCVD in a molecularly well-defined FH cohort, the SAFEHEART registry, which is a nationwide study based on data obtained from real-life practice. The differences between FH patients and unaffected relatives and FH patients with and without ASCVD are extensively described. Furthermore, this is the only work in which unaffected relatives are used as the control population. Our results also show how age, male sex, the presence of other cardiovascular risk factors (mainly increased body mass index, hypertension, T2DM, and smoking habit), and Lp(a) >50 mg/dL are independently associated to ASCVD in FH patients. LDL-C association with ASCVD was not assessed because the baseline lipid profile (without treatment) was not available in a huge number of patients and, in concrete, among those patients with previous ASCVD. Nevertheless, LDL-C level is the principal prognostic marker in FH patients and always should be considered to establish risk assessment.
Recent data from the CASCADE FH registry in the United States have shown a high prevalence of ASCVD. However, the main difference with SAFEHEART is the inclusion criteria of FH patients. In SAFEHEART, all cases registered have been analyzed using DNA testing, and in CASCADE, only 3% had molecular confirmation. On the contrary, there were not uniform clinical criteria used by specialists in United States.10 There are also differences in the prevalence of other cardiovascular risk factors, such as hypertension, T2DM, and mean age at inclusion.
The estimated risk of ASCVD among patients with FH has been previously described by Benn et al9 in a population-level survey undertaken in Denmark. This study reported an OR of 13.2 (10.0–17.4) for FH patients not receiving LLT and 10.3 (7.8–13.8) for FH patients receiving LLT, compared with patients who do not have FH and are not receiving LLT. Our group previously conducted a cross-sectional study on 811 FH patients to estimate the risk factors associated with the development of premature ASCVD.11 The authors compared the results from this registry with the overall Spanish population. Their data show a calculated 8.4-fold increased cardiovascular risk. Nevertheless, in that study, only index cases were included and only premature ASCVD was considered.
Prevalence of risk factors different to elevated LDL-C levels as well as their management and impact likely differ between FH patients and non-FH patients.12 The OR found for the presence of ASCVD in the present study was smaller than those previously described. Probably, the reason for that is the high prevalence of other cardiovascular risk factors different to elevated LDL-C plasma levels present in the unaffected relatives population enrolled. As can be seen, the prevalence of active smoking is significantly higher among unaffected relatives than among FH patients with ASCVD. This finding presumably reflects the perceived importance about their disease that FH patients feel and the impact that their physicians’ advice causes in their lifestyle. An interesting point is the lack of significant differences found in the prevalence of familial history of premature ASCVD. It is well understood if we keep in mind that all the enrolled subjects, with and without the mutation, belong to the same families.
Recently, it has been published the risk of coronary artery disease on the presence or absence of a mutation related with FH in coronary artery disease case–control studies showing an OR of 22 in subjects with a FH mutation and LDL-C of >190 mg/dL compared with those with LDL-C of <130 mg/dL and no mutation. After adjusting for LDL-C levels, the OR was 4.2, slightly higher than that in our study.13 Besides differences in the design and analyzed population between both studies, the prevalence of other cardiovascular risk factors like T2DM, hypertension, current smokers, and mean age is higher in the study by Khera et al.13 This fact could explain the difference in coronary artery disease risk.
FH is known to be associated with elevated LDL-C levels and increased risk of premature coronary heart disease.2,3 Because increased LDL-C levels lead to atherosclerosis, FH has also been proposed as a risk factor for peripheral vascular and ischemic cerebrovascular diseases.4,14 Currently, the association between clinical FH and risk of stroke is unclear. Some studies, focused on estimating the stroke risk, have provided limited data, because of the lack of a control group, the small sample size, and the lack of a molecular diagnosis.4,15 A prospective study of FH by the United Kingdom–based Simon Broome Register Group did not find an increased risk of stroke mortality for subjects with FH.16 By contrast, the prevalence of peripheral arterial disease is increased from 5- to 10-fold in FH subjects compared with non-FH controls.4,17 Our data show a clearly increased prevalence of coronary heart disease among those patients with FH and an increased prevalence of peripheral artery disease when compared with their unaffected relatives. Among those patients with ASCVD, 13.7% FH patients and 31.9% unaffected relatives had cerebrovascular involvement. Nevertheless, in our study, no significant differences were found for atherosclerotic cerebrovascular disease prevalence between FH patients and their relatives. Once more, the different prevalence of cardiovascular risk factors different to elevated LDL-C plasma levels might have played a role for not achieving differences between both groups. A better understanding of the association between FH and the incidence of atherosclerotic cerebrovascular disease–related events could have a public health impact by improving the diagnosis and management of individuals with FH.
Interestingly, our results might show a decreased prevalence of ASCVD when compared with prestatin era studies, as the effective LDL-C lowering achieved by statins and ezetimibe is associated with a significant reduction in the prevalence of ASCVD.18,19
Strengths and Limitations
We acknowledge some strengths and limitations of our study. To our knowledge, this is the largest study of a molecularly characterized heterozygous FH population that describe the development of atherosclerotic lesions in the heart, brain, and peripheral arteries. A potential limitation is the fact that only clinical events have been considered; the detection of subclinical atherosclerotic disease might have room to improve the management of these patients. This is a large follow-up study of FH patients in which no intervention different to the provided by the patient’s physician was done. Thus, a reliable baseline lipid profile in this registry is missing because some patients were already on treatment when they were enrolled. This work compares genetically defined FH patients with their genetically confirmed non-FH relatives, who are not completely free from other lipid disorders such as combined familial hypercholesterolaemia or polygenic hypercholesterolaemia.
This study shows the high prevalence of ASCVD and the differential involvement of the arterial territories in FH patients when compared with their unaffected relatives. Age, male sex, increased body mass index, hypertension, T2DM, smoking habit, and Lp(a) of >50 mg/dL were independently associated with the presence of ASCVD, not forgetting LDL-C level as the a principal driver for its development.
We thank the Spanish Familial Hypercholesterolemia Foundation for assistance in the recruitment and follow-up of participants and to the familial hypercholesterolemia families for their valuable contribution and willingness to participate. SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) investigators who have participated in patient recruitment and data collection: Rocío Aguado (Hospital Universitario de León); Fátima Almagro (Hospital Donostia, San Sebastián); Francisco Arrieta (Hospital Ramón y Cajal, Madrid); Miguel Ángel Barba (Hospital Universitario, Albacete); Ángel Brea, Daniel Mosquera (Hospital San Pedro, Logroño); Jose María Cepeda (Hospital de Vega Baja, Orihuela); Raimundo De Andrés (Fundación Jiménez Díaz, Madrid); Gonzalo Díaz (Hospital Clínico, Valladolid); José L. Díaz (Hospital Abente y Lago, A Coruña); Francisco Fuentes, José Lopez-Miranda (Hospital Reina Sofía, Córdoba); Jesús Galiana (Hospital de Ciudad Real); Juan Antonio Garrido (Hospital de Ferrol); Luis Irigoyen (Hospital Clínico Universitario Lozano Blesa, Zaragoza); Laura Manjón (Hospital de Cabueñes, Gijón); Alberto Martin, Mar Piedecausa (Hospital Universitario de Elche); Ceferino Martínez-Faedo (Hospital Central de Asturias, Oviedo); Marta Mauri (Hospital de Terrassa, Barcelona); Pablo Miramontes (Hospital Clínico Universitario, Salamanca); Ovidio Muñiz (Hospital Virgen del Rocío, Sevilla); Francisca Pereyra (Hospital Universitario Nta. Sra Candelaria, Tenerife); Leire Pérez (Hospital Universitario de Álava); Xavier Pintó (Hospital de Bellvitge, Barcelona); Pedro Pujante (Hospital Vital Álvarez Buylla, Mieres); Enrique Ruiz (Hospital Universitario, Burgos); Pedro Sáenz (Hospital de Mérida); Juan F. Sánchez (Hospital San Pedro de Alcántara, Cáceres); Jose I. Vidal, Rosa Argüeso (Hospital Universitario, Lugo); Daniel Zambón (Hospital Clinic, Barcelona); Lina Badimón, Teresa Padró (Instituto Catalán de Ciencias Cardiovasculares, Barcelona).
Sources of Funding
This work was supported by Fundación Hipercolesterolemia Familiar; grant G03/181 and FIS PI12/01289 from Instituto de Salud Carlos III, grant 08 to 2008 Centro Nacional de Investigación Cardiovascular.
Dr Perez de Isla reports personal fees from Merck, Sharp and Dohme, personal fees from Astra Zeneca, outside the submitted work. Dr Alonso reports personal fees from AMGEN, personal fees from AEGERION, personal fees from ISIS, outside the submitted work. Dr Mata received honoraria for advisory boards and received research grants from Amgen and Sanofi. The other authors report no conflicts.
The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.116.307514/-/DC1.
- Nonstandard Abbreviations and Acronyms
- atherosclerotic cardiovascular disease
- confidence interval
- heterozygous familial hypercholesterolemia
- high-density lipoprotein cholesterol
- low-density lipoprotein cholesterol
- LDL receptor
- lipid-lowering therapy
- odds ratio
- type 2 diabetes mellitus
- Received March 9, 2016.
- Accepted July 6, 2016.
- © 2016 American Heart Association, Inc.
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Prevalence of ASCVD in FH patients is high and the involvement of the arterial territories is different to that of their unaffected relatives.
Age, male sex, increased body mass index, hypertension, T2DM, smoking habit, and Lp(a) of >50 mg/dL were independently associated with the presence of ASCVD.
LDL-C level remains the principal driver for ASCVD development.