Objective. To determine the contribution of classical risk factors to the development of cardiovascular disease (CVD) in patients with heterozygous familial hypercholesterolaemia (FH). Design. A retrospective, multi-centre, cohort study. Extensive data were collected by scrutinizing medical records and the use of questionnaires. Multivariate Cox regression was used to study the relationship between potential risk factors and the occurrence of CVD. Setting and subjects. We included 2400 FH patients from 27 Dutch lipid clinics. The diagnosis of FH was based upon the presence of a low-density lipoprotein receptor mutation or upon strict clinical criteria.
Main outcome measures. Cardiovascular mortality and CVD.Results. During 112.943 person-years, 782 (32.6%) patients had had at least one cardiovascular event. Male gender (RR 2.82, 95% CI 2.37-3.36), smoking (RR 1.67, 95% CI 1.40-1.99), hypertension (RR 1.36, 95% CI 1.06-1.75), diabetes mellitus (RR 2.19, 95% CI 1.36-3.54), low HDL-C (RR 1.37, 95% CI 1.15-1.63) and elevated lipoprotein(a) levels (RR 1.50, 95% CI 1.20-1.79) proved to be independent CVD risk factors. These six risk factors explained 18.7% of the variation in the occurrence of CVD. Conclusions. Male gender, smoking, hypertension, diabetes mellitus, HDL cholesterol and lipoprotein(a) levels proved to be important risk factors for CVD in FH patients. In addition to the routine institution of statin therapy, controlling these factors needs special attention in the management of this disorder.
A minority of U.S. medical schools from which information was obtained requires training in palliative care and evaluates students in their care of patients with advanced, incurable conditions. Most medical schools have chosen to include palliative care topics within existing courses. AAMC's existing database does not assess the scope or extent of coursework and rotations in palliative care. Guidelines are needed that address palliative care education and training of medical students.
Despite the use of stringent clinical criteria to define FH patients, two cohorts could be identified within our study population, namely those patients with and those without an LDLR mutation. Our findings suggest that among those without an LDLR mutation, patients with other causes of dyslipidaemia may be present. These observations underline the relevance of genetic testing in FH for clinical practice, for screening purposes, and for research involving these patients.
Objective-To investigate the contribution of polymorphisms in multiple candidate genes to cardiovascular disease (CVD) risk in a large cohort of patients with heterozygous familial hypercholesterolemia (FH). (FH) is a common hereditary disease, characterized by elevated levels of plasma low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease (CVD). 1 Characteristically, the mean age of onset of CVD is between 40 and 45 years in male FH patients and in female FH patients 10 years later. 1,2 Nevertheless, the phenotypic expression of this disorder, in terms of onset and severity of atherosclerotic vascular disease, varies considerably. 3 Unfortunately, a paucity of solid data exists on factors that contribute to these phenotypic differences. Previous studies have mostly focused on classical CVD risk factors and the functional variety among LDL receptor mutations. 4 -6 Although both influence the occurrence of CVD, they can only partially explain the observed large differences. We recently studied the contribution of classical risk factors to CVD in a large cohort of FH patients and demonstrated that Ͻ20% of the variation in CVD occurrence could be explained by these risk factors alone. 7 Therefore, other still unknown and possibly genetic factors play an undeniable role in the development of CVD in these patients. Genetic differences affect susceptibility to disease and whereas premature atherosclerosis can be linked in rare cases to single-gene disorders, most individuals do not carry such DNA defects. The "common disorder, common variant" theory predicts that the majority of population-attributable variation in susceptibility to prevalent disease is caused by variants that occur in high frequency in multiple genes. 8 Such genetic variation may also play an important role in the development of CVD in FH. This is substantiated by the fact that clustering of CVD occurs in FH kindred. 9 Unfortunately, large-scale association studies involving multiple polymorphisms are lacking in FH. Our objective, therefore, was to investigate the contribution of polymorphisms in multiple candidate genes to CVD risk in a large cohort of patients with heterozygous FH.
Methods and Results-We
Methods
Study Design and Study PopulationThe present investigation was a retrospective, multicenter, cohort study. The study design and study population have been described elsewhere. 7 Briefly, lipid clinics in the Netherlands submit DNA samples from clinically suspected FH patients to a central laboratory for LDL receptor mutation analysis. 10 We randomly selected hypercholesterolemic patients from this DNA bank database with the aid of a computer program (Microsoft Excel). These patients had been referred from 27 lipid clinics throughout the Netherlands ( Figure I, available online at http://atvb.ahajournals.org).Phenotypic data (including detailed information on CVD) were acquired by reviewing patient's medical records by a trained team of data collectors. 7 Guidelines for data collection from medical records were ...
Heterozygous familial hypercholesterolemia (FH) is a common inherited disorder of lipoprotein metabolism. FH is characterized by elevated levels of low-density lipoprotein cholesterol, the presence of tendon xanthomas, and premature cardiovascular disease. The underlying molecular defect of FH consists of mutations in the gene coding for the low-density-lipoprotein-receptor protein, detection of which provides the only unequivocal diagnosis. Although the cause of FH is monogenic, there is wide variation in the onset and severity of atherosclerotic disease in these patients. Additional atherogenic risk factors of environmental, metabolic, and genetic origin are presumed to influence the clinical phenotype in FH. Criteria used to identify individuals with FH include a combination of clinical characteristics, personal and family history of early coronary artery disease, and biochemical parameters. Since the introduction in 1989 of statins, which have been shown to be effective and to delay or prevent the onset of cardiovascular disease, drug treatment of FH has greatly improved. New lipid-lowering agents are presently being developed for clinical use. This review provides an update on the clinical, diagnostic, and therapeutic aspects of heterozygous familial hypercholesterolemia.
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