Heterozygous familial hypercholesterolemia (FH) is an autosomal dominant disorder known to be associated with elevated cholesterol levels and increased risk of premature coronary heart disease. Since increased cholesterol levels lead to atherosclerosis, FH has also been proposed as a risk factor for peripheral vascular and ischemic cerebrovascular disease. Currently, the association between clinical FH and risk of stroke is unclear: Two studies conducted in the 1980s indicated an increased risk of stroke in FH subjects; however, two others found no higher risk, and all had methodological limitations. A recent prospective study of familial hypercholesterolemia by the United Kingdom-based Simon Broome Register Group did not find an excess risk of stroke mortality for subjects with clinical FH. By contrast, the prevalence of peripheral arterial disease is increased from five- to 10-fold in FH subjects compared with non-FH controls. In addition, the intima-media thickness of the carotid and/or femoral artery is increased in FH subjects. Better understanding of the association between FH and the incidence of ischemic stroke events could have a public health impact by improving the diagnosis, prognosis, and treatment of individuals with FH and their relatives and by elucidating the relation between cholesterol levels and ischemic cerebrovascular disease.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder affecting approximately one of 500 Caucasians (1). The clinical phenotype is marked by elevated cholesterol levels, tendinous xanthomata, and a family history of premature coronary disease, and the phenotype is considerably more severe for homozygotes than heterozygotes (2). The clinical FH phenotype was first shown to result from mutations in the low density lipoprotein receptor gene (LDLR) (3, 4) located on chromosome 19p13.1-p13.3 (5). The FH clinical phenotype can also result from the mutations in the apolipoprotein B-100 gene (APOB) (6, 7), located on chromosome 2p23-24 (8–10). Recent work has localized a third gene, proprotein convertase subtilisin/kexin type 9 (PCSK9), associated with the clinical FH phenotype (11). This gene is located on chromosome 1p34.1-p32 and encodes NARC-1, a novel proprotein convertase (11).

Two mutations in APOB (R3500Q and R3500W) (7, 12) and over 700 mutations in LDLR (13, 14) have been identified in studies of individuals with a clinical FH phenotype. The prevalence of these mutations in FH subjects from different populations and ethnic groups has been reviewed for the Human Genome Epidemiology Network (15), while the PCSK9 gene has not yet been studied at the population level. The prevalence review showed that there are a few founder populations in which a small number of mutations predominate, but most populations have a large spectrum of distinct LDLR mutations among FH individuals, with each mutation found in only a small number of individuals (15). Furthermore, studies often fail to detect the underlying mutation in 15–40 percent, or more, of the subjects screened for LDLR and APOB, indicating additional genetic and/or environmental causes for the FH phenotype (15).

Cerebrovascular disease and peripheral vascular disease are both composite terms that encompass a number of phenotypes and etiologic pathways. These conditions fall under the broader category of cardiovascular disease, along with coronary heart disease. The relation between FH and coronary heart disease is reviewed separately (16).

Cerebrovascular disease and its clinical manifestation of stroke comprise ischemic stroke (cerebral thrombosis and cerebral embolisms) and hemorrhagic stroke (cerebral hemorrhage and subarachnoid hemorrhage) (17), and these categories can be further divided into heterogeneous subtypes (18). Stroke is the third leading cause of death in the United States (17) and is a leading cause of death worldwide (19). Stroke is also a major cause of morbidity in Western countries (17), with over 1 million American adults reporting long-term disabilities due to stroke events (20).

Peripheral vascular disease is defined by the American Heart Association as "diseases of blood vessels outside of the heart and brain" (17, p. 26). This review follows that definition and includes the extracranial carotid vessels. Peripheral arterial disease, the most common form of peripheral vascular disease, results from atheroslerotic buildup in the peripheral arteries (17), with clinical manifestations ranging from intermittent claudication (leg pain during exercise) to critical limb ischemia, gangrene, and amputation (21). Peripheral arterial disease affects approximately 27 million people in Europe and North America (22), and it is a strong predictor of morbidity and mortality (22). Often asymptomatic and underdiagnosed, the public health significance of peripheral arterial disease should not be underestimated (21, 23). The risk of death within 10 years is sixfold higher for symptomatic and asymptomatic peripheral arterial disease patients compared with patients without peripheral arterial disease (21).

According to recent reviews (17,23), the risk factors for both cerebrovascular disease and peripheral vascular disease include smoking, diabetes, advanced age, male gender, hypertension, hyperlipidemia, family history of cardiovascular disease, and prior heart or vascular disease. Therefore, as a predictor of elevated cholesterol levels, FH seems a logical risk factor for both peripheral vascular disease and cerebrovascular disease. The association between elevated cholesterol levels and disease risk is fairly well established for peripheral arterial disease as an atherosclerotic disease (21) and, while cholesterol is not thought to be associated with hemorrhagic stroke events, it is traditionally listed as a potential risk factor for ischemic stroke (17).

However, current literature does not fully support the paradigm of elevated cholesterol levels as a risk factor for stroke events. An investigation of 10-year trends in the incidence and mortality of coronary heart disease and stroke in 15 populations worldwide showed that trends in stroke and heart disease differ, implying differences in underlying risk factors (24), with one possibility being that cholesterol is a strong risk factor for coronary heart disease but not for stroke. In addition, the results of several recent large-scale cohort studies indicate that cholesterol levels are not associated with ischemic stroke events (25, 26). This is in contrast to the results of other observational studies that have found an association between cholesterol levels and stroke (27, 28) and to the results of clinical trials of statins that have demonstrated that the decrease in cholesterol levels is accompanied by a decrease in the risk of stroke events (29), although it had been suggested that this may be due to cholesterol-independent actions of statins (30). Since individuals with clinical FH have roughly twofold elevated cholesterol levels from birth until diagnosis and treatment and they often continue to have elevated cholesterol levels even when treated (31), studies of stroke risk in FH subjects will contribute to this debate.

To identify epidemiologic studies of FH, stroke, and peripheral arterial disease, we searched MEDLINE and PubMed using combinations of the terms "familial hypercholesterolemia," "LDLR" [low density lipoprotein receptor], "apolipoprotein B" ("APOB"), "stroke," "cerebrovascular disease," "peripheral vascular disease," "peripheral arterial disease," and "intima-media thickness." Articles were identified through September 2003. We identified additional studies by reviewing the reference lists of all retrieved articles.

Stroke events
Epidemiologic studies of the association of the clinical FH phenotype with stroke events by geographic location are summarized in Web table 1. (This information is described in the first of three supplementary tables; each is referred to as "Web table" in the text and is posted on the website of the Human Genome Epidemiology Network (http://www.cdc.gov/genomics/hugenet/reviews.htm) as well as on the Journal’s website.) Three studies conducted in the 1980s had contrasting results. A Finnish study prospectively followed 54 subjects with clinical FH (34 men and 20 women aged 21–50 years) for an average of 10 years (32). The incidence of brain infarction was 7.4/1,000 years, a level 20 times that of the general population (32). Unfortunately, the study lacked a defined control group so there was potential for surveillance bias. Specifically, since physicians were closely following the FH subjects, the FH subjects may be more likely to be diagnosed with cerebrovascular disease. Furthermore, a large proportion (77 percent) of the patients had preexisting coronary heart disease or cerebrovascular disease at entry into the study (32). Such patients may represent individuals with more severe forms of FH, and thus the results are likely to be biased.

A case-only study in India examined 25 young patients (15 males and 10 females aged 9–38 years) with cerebral infarction of unknown etiology (33). Examination of the patients found 15 to be hyperlipidemic, nine with familial forms of the disease. Further examination of family members showed that two of the 25 (8 percent) had pedigrees indicative of FH (33). Again, the study lacked a control group, but the prevalence of FH in stroke survivors was higher than that of the general population and was similar to early findings that 5 percent of myocardial infarction survivors have FH (34, 35).

A Japanese study prospectively followed 15 individuals with homozygous FH and 527 individuals with heterozygous FH (36). Forty-one heterozygous individuals died during the 10-year follow-up, including four from cerebrovascular events. The study calculated proportional mortality, using autopsy reports, hospital records, and physician interviews, to determine the proportion of deceased individuals who died from stroke. The observed proportional mortality for strokes of 9.8 percent was similar to the proportional mortality for stroke events based on census information in the general Japanese and British populations (36). These results complemented an earlier cross-sectional study in Norway, which also found mortality for cerebrovascular disease to be lower in xanthomata patients (likely FH heterozygotes) compared with that in the general population (37).

The contrasting results from these three studies from the 1980s may be due to spurious results due to small sample sizes, and they may also be due to differences in the endpoints measured. The first two studies (32, 33) examined young adults who survived incident cases of ischemic stroke, and they found an association between FH and stroke. In contrast, the third study (36) examined overall mortality from stroke and did not find an association. Given the large competing risk of death due to coronary disease, studies of cerebrovascular mortality are likely to underestimate the actual risk of disease in FH patients (38). Further, the inclusion of hemorrhagic strokes, which are not associated atherosclerosis, could attenuate the observed association toward the null.

A more recent Danish study examined 36 female and 44 male patients with ischemic stroke events before 50 years of age (39). Patients were screened for five LDLR mutations known to be common in the Danish population and for three mutations in APOB. None of the subjects was found to carry a mutation in either gene (39). However, since less than 50 percent of clinical FH patients in Denmark carry one of these eight mutations, this does not completely rule out the possibility of FH among the stroke patients studied (40). The authors noted a higher mean cholesterol level for the stroke cases compared with a control group of 3,366 individuals from the general Danish population, and they postulated that some patients might have rare LDLR mutations (39). Ideally, future studies of molecular causes of FH will comprehensively screen for mutations in LDLR, APOB, and PCSK9.
A recent well-designed study by the United Kingdom-based Simon Broome Familial Hypercholesterolemia Register Group followed 1,405 men and 1,466 women prospectively from 1980 to 1998 for 22,992 person-years (38). All participants were diagnosed with clinical FH, and the mean age at registration was 42.3 years. A total of nine deaths from stroke were observed. This number is similar to the 11.4 deaths expected based on 5-year age and 5-year calendar year mortality rates for stroke in the general population of England and Wales. The estimated relative risk, presented as a standardized mortality ratio, was 0.79 (95 percent confidence interval: 0.36, 1.50), indicating no excess risk of death from stroke for subjects with clinical FH (38). The proportional mortality for stroke was also similar to that of the general population. As noted in their paper, interpretation of these results is limited by low statistical power resulting from the small number of events observed, the use of stroke mortality rather than ischemic stroke incidence as the endpoint, and the widespread use of statins in the population. Further analysis did not note a difference in the standardized mortality ratio for the pre- and post-statin eras (38), whereas coronary heart disease deaths were approximately halved (41).

Peripheral arterial disease
Early studies of clinical manifestations of FH reported the prevalence of symptomatic peripheral arterial disease, as indicated by intermittent claudication, to be 8–16 percent in clinical FH heterozygotes (42–44). The use of echo-Doppler methods in the 1980s allowed for presymptomatic assessment of arterial lesions and measures of reduced blood flow. Using this method, two studies identified prevalent peripheral arterial disease in 30–45 percent of FH patients, with the severity increasing with age (45, 46).

Several other studies have also reported that the prevalence of peripheral arterial disease is greatly increased in FH subjects relative to non-FH controls (Web table 2). An Italian study of 62 FH patients (13 homozygous and 49 heterozygous) and 50 controls of similar age found a fivefold increase in arterial lesions in iliac arteries and an increase of from threefold to fourfold in the prevalence of reduced blood flow in the leg arteries (47). A small Finnish study of 20 FH patients and 20 age- and sex-matched controls found an abnormal ankle/arm blood pressure ratio in 65 percent of the cases compared with only 5 percent of the controls (48). Similar results were found in a 1995 study of 72 FH subjects in the Netherlands (49). This study noted a nearly 10-fold increase in the prevalence of peripheral arterial disease measured by ankle/arm blood pressure ratios and femoral artery blood flow in FH patients (31 percent) compared with age-, sex-, weight-, smoking-, and hypertension-matched controls (3.7 percent). Peripheral vascular disease was apparent in FH heterozygotes as young as 30 years, and, contrary to the pattern for coronary heart disease, the age of onset of peripheral arterial disease was similar for males and females (49).

Intima-media thickness
Since the 1990s, a frequent surrogate measure of peripheral arterial disease is the intima-media thickness of the carotid and/or femoral artery. This noninvasive measurement can identify preclinical stages of atherosclerosis, and large-scale epidemiologic studies have shown an association between increased intima-media thickness and future coronary heart disease and stroke events (50, 51). As a result, intima-media thickness is often presented as an intermediate phenotype in studies of cardiovascular disease (50–54) in the general population.

Studies of 53 Swedish FH subjects and 53 age-, height-, and sex-matched controls showed that the intima-media thickness of both the femoral and carotid arteries is increased for FH subjects (55, 56). These results have been corroborated by additional studies that have shown an increase of from 1.17-fold to 1.52-fold in common carotid intima-media thickness for FH individuals versus both normolipidemic (57–61) and hyperlipidemic (62, 63) controls (Web table 3). Two studies did not find a significant increase in the common carotid intima-media thickness; however, both noted other signs of arterial disease in FH patients (60, 64). A French study of FH children (64) found increased stiffness in the common carotid artery, and a Norwegian study (60) found an increase in carotid bifurcation intima-media thickness (in millimeters) for both men (FH subjects: mean = 0.81, standard deviation (SD) = 0.15; controls: mean = 0.74, SD = 0.19) and women (FH subjects: mean = 0.74, SD = 0.17; controls: mean = 0.66, SD = 0.15).

Intima-media thickness can also serve as an intermediate phenotype for cardiovascular risk in FH subjects. For example, a study of 248 FH subjects in the Netherlands found that intima-media thickness levels were predictive of coronary heart disease severity (65), with the mean intima-media thickness higher in FH subjects with coronary heart disease than in subjects without coronary heart disease. As an intermediate phenotype, intima-media thickness has been used as a marker to study environmental and genetic risk factors within FH individuals. Family history (62), gender (60, 66), lipoprotein levels (62, 66, 67), underlying LDLR mutation (63), and the paraoxonase 1 (PON1) gene (68) have all been shown to be associated with increased intima-media thickness and, by extension, are postulated as risk factors for cardiovascular disease, including clinical manifestations of cerebrovascular disease and peripheral vascular disease, in FH subjects.

Intima-media thickness has also been used to evaluate treatment regimens for FH. For example, a clinical trial comparing two different statin regimens in 325 patients with FH found that the decreased low density lipoprotein cholesterol levels were accompanied by decreased intima-media thickness, particularly in the group randomized for the more aggressive treatment (69). Similar results have been found in observational studies, with a regression of carotid intima-media thickness being noted in patients undergoing treatment with statins (59, 70–72). However, as with any intermediate phenotype, caution should be used when extrapolating from measures of intima-media thickness to predictions of risk for future coronary heart disease or cerebrovascular events. Of concern is the fact that treatments might alter intima-media thickness levels without impacting cardiovascular disease risk.

This project was supported under a cooperative agreement from the Centers for Disease Control and Prevention through the Association of Schools of Public Health (grants U36/CCU300430-20 and U36/CCU300430-22). This research was also supported by National Institutes of Health grant HL-49513 from the National Heart, Lung, and Blood Institute. S. E. H. is supported by the British Heart Foundation and in part by a grant from the Department of Health and Departments of Trade and Industry to the London Genetics Knowledge Park.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Association of Schools of Public Health.

Correspondence to Dr. Melissa A. Austin, F 363 Health Sciences Building, Box 357236, School of Public Health and Community Medicine, University of Washington, 1959 NE Pacific Avenue, Seattle, WA 98195 (e-mail: maustin@u.washington.edu).

Web tables and Appendix for web tables:

• Web Table 1 - Association studies of clinical familial hypercholesterolemia (FH) and stroke, by geographic location
• Web Table 2 - Association studies of clinical familial hypercholesterolemia (FH) and peripheral arterial disease (PAD), by geographic location
• Web Table 3 - Summary of studies comparing intima-media thickness (IMT) in familial hypercholesterolemia (FH) subjects vs. controls, by geographic location
• Appendix

1. Goldstein JL, Hazzard WR, Schrott HG, et al. Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction. J Clin Invest 1973;52:1533–43.
2. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Sly WS, Childs B, et al, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York, NY: McGraw-Hill Companies, Inc, 2001.
3. Goldstein JL, Brown MS. Binding and degradation of low density lipoproteins by cultured human fibroblasts. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J Biol Chem 1974;249:5153–62.
4. Brown MS, Goldstein JL. Expression of the familial hypercholesterolemia gene in heterozygotes: mechanism for a dominant disorder in man. Science 1974;185:61–3.
5. Lindgren V, Luskey KL, Russell DW, et al. Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3- methylglutaryl-coenzyme A reductase with cDNA probes. Proc Natl Acad Sci U S A 1985;82:8567–71.
6. Innerarity TL, Weisgraber KH, Arnold KS, et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci U S A 1987;84:6919–23.
7. Soria LF, Ludwig EH, Clarke HR, et al. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci U S A 1989;86:587–91.
8. Knott TJ, Rall SC Jr, Innerarity TL, et al. Human apolipoprotein B: structure of carboxyl-terminal domains, sites of gene expression, and chromosomal localization. Science 1985;230:37–43.
9. Law SW, Lee N, Monge JC, et al. Human ApoB-100 gene resides in the p23––pter region of chromosome 2. Biochem Biophys Res Commun 1985;131:1003–12.
10. Law SW, Lackner KJ, Hospattankar AV, et al. Human apolipoprotein B-100: cloning, analysis of liver mRNA, and assignment of the gene to chromosome 2. Proc Natl Acad Sci U S A 1985;82:8340–4.
11. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154–6.
12. Gaffney D, Reid JM, Cameron IM, et al. Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. Arterioscler Thromb Vasc Biol 1995;15:1025–9.
13. Heath KE, Gahan M, Whittall RA, et al. Low-density lipoprotein receptor gene (LDLR) world-wide website in familial hypercholesterolaemia: update, new features and mutation analysis. Atherosclerosis 2001;154:243–6.
14. Villeger L, Abifadel M, Allard D, et al. The UMD-LDLR database: additions to the software and 490 new entries to the database. Hum Mutat 2002;20:81–7.
15. Austin MA, Hutter CM, Zimmern RL, et al. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 2004;160:407–420.
16. Austin MA, Hutter CM, Zimmern RL, et al. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol 2004;160:421–9.
17. Heart and stroke facts. Dallas, TX: American Heart Association, 2001.
18. Meschia JF. Addressing the heterogeneity of the ischemic stroke phenotype in human genetics research. Stroke 2002;33:2770–4.
19. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997;349:1269–76.
20. Heart and stroke statistics—2003 update. Dallas, TX: American Heart Association, 2003.
21. Belch JJ, Topol EJ, Angnelli G, et al. Critical issues in peripheral arterial disease detection and management. Arch Intern Med 2003;163:884–92.[Free Full Text]
22. Weitz JI, Byrne J, Clagett GP. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation 1996;94:3026–49.[Free Full Text]
23. Criqui MH. Peripheral arterial disease—epidemiological aspects. Vasc Med 2001;6:3–7.
24. Truelsen T, Mahonen M, Tolonen H, et al. Trends in stroke and coronary heart disease in the WHO MONICA Project. Stroke 2003;34:1346–52.
25. Shahar E, Chambless LE, Rosamond WD, et al. Plasma lipid profile and incident ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study. Stroke 2003;34:623–31.
26. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet 1995;346:1647–53.
27. Neaton JD, Wentworth DN, Cutler J, et al. Risk factors for death from different types of stroke. Multiple Risk Factor Intervention Trial Research Group. Ann Epidemiol 1993;3:493–9.
28. Hachinski V, Graffagnino C, Beaudry M, et al. Lipids and stroke: a paradox resolved. Arch Neurol 1996;53:303–8.
29. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.
30. Vaughan C. Prevention of stroke and dementia with statins: effects beyond lipid lowering. Am J Cardiol 2003;91:23B–9B.
31. Goldstein JL, Brown MS. Molecular medicine. The cholesterol quartet. Science 2001;292:1310–12.[Free Full Text]
32. Kaste M, Koivisto P. Risk of brain infarction in familial hypercholesterolemia. Stroke 1988;19:1097–100.
33. Bansal BC, Sood AK, Bansal CB. Familial hyperlipidemia in stroke in the young. Stroke 1986;17:1142–5.
34. Goldstein JL, Schrott HJ, Hazzard WR, et al. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest 1973;52:1544–68.
35. Patterson D, Slack J. Lipid abnormalities in male and female survivors of myocardial infarction and their first-degree relatives. Lancet 1972;1:393–9.
36. Mabuchi H, Miyamoto S, Ueda K, et al. Causes of death in patients with familial hypercholesterolemia. Atherosclerosis 1986;61:1–6.
37. Heiberg A, Berg K. The inheritance of hyperlipoproteinaemia with xanthomatosis. A study of 132 kindreds. Clin Genet 1976;9:203–33.
38. Huxley RR, Hawkins MH, Humphries SE, et al. Risk of fatal stroke in patients with treated familial hypercholesterolemia: a prospective registry study. Stroke 2003;34:22–5.
39. Frikke-Schmidt R, Arlien-Soborg P, Thorsen S, et al. LDL receptor mutations and ApoB mutations are not risk factors for ischemic cerebrovascular disease of the young, but lipids and lipoproteins are. Eur J Neurol 1999;6:691–6.
40. Jensen HK. The molecular genetic basis and diagnosis of familial hypercholesterolemia in Denmark. Dan Med Bull 2002;49:318–45.
41. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group. Atherosclerosis 1999;142:105–12.
42. Slack J. Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet 1969;2:1380–2.
43. Stone NJ, Levy RI, Fredrickson DS, et al. Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia. Circulation 1974;49:476–88.
44. Beaumont V, Jacotot B, Beaumont JL. Ischaemic disease in men and women with familial hypercholesterolaemia and xanthomatosis. A comparative study of genetic and environmental factors in 274 heterozygous cases. Atherosclerosis 1976;24:441–50.
45. Postiglione A, Rubba P, De Simone B, et al. Carotid atherosclerosis in familial hypercholesterolemia. Stroke 1985;16:658–61.
46. Kuo PT, Toole JF, Schaaf JA, et al. Extracranial carotid arterial disease in patients with familial hypercholesterolemia and coronary artery disease treated with colestipol and nicotinic acid. Stroke 1987;18:716–21.
47. Rubba P, De Simone B, Postiglione A, et al. Non-invasive evaluation of iliac and carotid atherosclerosis in familial hypercholesterolemia. Beitr Infusionsther 1988;23:33–8.
48. Perhoniemi V, Gylling H, Salmenkivi K. Peripheral atherosclerosis in familial hypercholesterolemia. J Intern Med 1989;225:379–83.
49. Kroon AA, Ajubi N, van Asten WN, et al. The prevalence of peripheral vascular disease in familial hypercholesterolaemia. J Intern Med 1995;238:451–9.
50. Bots ML, Hoes AW, Koudstaal PJ, et al. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997;96:1432–7.
51. Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol 1997;146:483–94.
52. Chambless LE, Folsom AR, Clegg LX, et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 2000;151:478–87.
53. Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;128:262–9.
54. Burke GL, Evans GW, Riley WA, et al. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. Stroke 1995;26:386–91.
55. Wendelhag I, Wiklund O, Wikstrand J. Arterial wall thickness in familial hypercholesterolemia. Ultrasound measurement of intima-media thickness in the common carotid artery. Arterioscler Thromb 1992;12:70–7.
56. Wendelhag I, Wiklund O, Wikstrand J. Atherosclerotic changes in the femoral and carotid arteries in familial hypercholesterolemia. Ultrasonographic assessment of intima-media thickness and plaque occurrence. Arterioscler Thromb 1993;13:1404–11.
57. Raal FJ, Pilcher GJ, Waisberg R, et al. Low-density lipoprotein cholesterol bulk is the pivotal determinant of atherosclerosis in familial hypercholesterolemia. Am J Cardiol 1999;83:1330–3.
58. Smilde TJ, van den Berkmortel FW, Boers GH, et al. Carotid and femoral artery wall thickness and stiffness in patients at risk for cardiovascular disease, with special emphasis on hyperhomocysteinemia. Arterioscler Thromb Vasc Biol 1998;18:1958–63.
59. Nolting PR, de Groot E, Zwinderman AH, et al. Regression of carotid and femoral artery intima-media thickness in familial hypercholesterolemia: treatment with simvastatin. Arch Intern Med 2003;163:1837–41.
60. Tonstad S, Joakimsen O, Stensland-Bugge E, et al. Carotid intima-media thickness and plaque in patients with familial hypercholesterolaemia mutations and control subjects. Eur J Clin Invest 1998;28:971–9.
61. Lavrencic A, Kosmina B, Keber I, et al. Carotid intima-media thickness in young patients with familial hypercholesterolaemia. Heart 1996;76:321–5.
62. Taira K, Bujo H, Kobayashi J, et al. Positive family history for coronary heart disease and ‘midband lipoproteins’ are potential risk factors of carotid atherosclerosis in familial hypercholesterolemia. Atherosclerosis 2002;160:391–7.
63. Descamps OS, Gilbeau JP, Leysen X, et al. Impact of genetic defects on atherosclerosis in patients suspected of familial hypercholesterolaemia. Eur J Clin Invest 2001;31:958–65.
64. Aggoun Y, Bonnet D, Sidi D, et al. Arterial mechanical changes in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2000;20:2070–5.
65. Wittekoek ME, de Groot E, Prins MH, et al. Differences in intima-media thickness in the carotid and femoral arteries in familial hypercholesterolemic heterozygotes with and without clinical manifestations of cardiovascular disease. Atherosclerosis 1999;146:271–9.
66. Brorholt-Petersen JU, Jensen HK, Jensen JM, et al. LDL receptor mutation genotype and vascular disease phenotype in heterozygous familial hypercholesterolaemia. Clin Genet 2002;61:408–15.
67. Tonstad S, Leren TP, Sivertsen M, et al. Determinants of lipid levels among children with heterozygous familial hypercholesterolemia in Norway. Arterioscler Thromb Vasc Biol 1995;15:1009–14.
68. Leus FR, Wittekoek ME, Prins J, et al. Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia. Atherosclerosis 2000;149:371–7.
69. Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357:577–81.
70. Smilde TJ, van den Berkmortel FW, Wollersheim H, et al. The effect of cholesterol lowering on carotid and femoral artery wall stiffness and thickness in patients with familial hypercholesterolaemia. Eur J Clin Invest 2000;30:473–80.
71. Spacil J, Ceska R, Petrasek J, et al. The effect of four-year hypolipidaemic treatment on the intimal thickness of the common carotid artery in patients with familiar hyperlipidaemia. Int Angiol 1999;18:313–19.
72. Wendelhag I, Wiklund O, Wikstrand J. Intima-media thickness after cholesterol lowering in familial hypercholesterolemia. A three-year ultrasound study of common carotid and femoral arteries. Atherosclerosis 1995;117:225–36.

• MedPed Coordinating Center at the University of Utah (last accessed 2/2008): More about familia hypercholesterolemia
• Center for Genetic Education: Familial Hypercholesterolaemia and Cardiovascular Disease
• Mortality from Familial Hypercholesterolaemia (last accessed 2/2008)
  Online presentation by Eric Sijbrands, Erasmus Univeristy Medical Center , Rotterdam , Denmark
• GeneCards: LDLR (last accessed 2/2008)
• GeneCards: APOB (last accessed 2/2008)