The Spanish Familial Hypercholesterolaemia Cohort Study

Обзор

SAFEHEART is a large, on-going registry study in molecularly defined patients with heterozygous FH treated in Spain.

Подробное описание

Familiar hypercholesterolemia (FH) is the most common genetic disorder associated with the development of severe and premature coronary artery disease (CAD). The disorder is caused by mutations in the gene that encodes the low-density lipoprotein receptor (LDL-r), resulting in a lower expression of functional LDL-r in the liver. FH has autosomal dominant transmission with high penetrance and the prevalence of heterozygous individuals is one in 400 to 500 in the general population. To date, more than 800 different functional mutations of the LDL-r gene have been described worldwide, and more than 200 have been documented in Spain. In addition, a much less common disorder that resemble FH is familial defective apoB 100 disorder (FDB) produced by a mutation in the Apo B 100 gene. FDB accounts for a significant proportion of FH in some localized regions of Spain.

Life expectancy is shortened by 20 to 30 years in FH patients, and sudden death and myocardial infarction are the principal causes of death. The Simon Broome Register of FH in Great Britain, has shown that FH has a 100-fold increase in coronary mortality and a nearly 10-fold increase in total mortality, especially in young adults.

Since the 1990's, coronary mortality and total mortality in FH patients have decreased remarkably in part due to the use of more effective lipid-lowering therapy such as statins. The analysis of the Dutch FH cohort showed that an early treatment with statins after the diagnosis of the disorder leads to near normalisation of coronary heart disease risk comparable to the general population. Therefore, most of patients require an early, continuous and more intensive lipid-lowering therapy.

Despite the use of statins, this population still have a high risk for the development of premature CAD. Therefore, the need to study the relatives of a known FH case, know as cascade screening, is essential to detect those cases that are younger, probably with a less severe form of FH and are not receiving treatment to prevent cardiovascular disease development.

Although the genetic defect is probably the most important factor in the clinical expression of FH, other genetic (gene-gene interactions), environmental (particularly those relating to diet, tobacco consumption and physical activity) and metabolic factors could play an important role in modulating the atherosclerotic burden in this population.

To gain insight into the prognostic factors and mechanisms that influence the development of CAD and mortality in FH, a long-term prospective follow-up of a molecularly well-defined FH cohort using a multidisciplinary approach is necessary. This cohort is an excellent tool of translational research to evaluate and determine the principal prognostic factors related to CAD morbidity and mortality.

Первичные конечные точки

• Prognostic assessment: time to fatal or non-fatal cardiovascular event. [Срок оценки: up to 12 years]

Вторичные конечные точки (1)

• LDL-cholesterol level (mg/dl) at entry and at follow-up [Срок оценки: up to12 years]

Критерии участия

Критерии включения

• Index cases with genetic diagnosis of FH and their relatives over 15 years old with a genetic diagnosis of FH and their first-degree relatives

Критерии исключения

• Patient unwillingness

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Испания · 1 центр

• Fundacion Hipercolesterolemia Familiar — Madrid

Публикации

• Vallejo-Vaz AJ, Kondapally Seshasai SR, Cole D, Hovingh GK, Kastelein JJ, Mata P, Raal FJ, Santos RD, Soran H, Watts GF, Abifadel M, Aguilar-Salinas CA, Akram A, Alnouri F, Alonso R, Al-Rasadi K, Banach M, Bogsrud MP, Bourbon M, Bruckert E, Car J, Corral P, Descamps O, Dieplinger H, Durst R, Freiberger T, Gaspar IM, Genest J, Harada-Shiba M, Jiang L, Kayikcioglu M, Lam CS, Latkovskis G, Laufs U, L PMID 26408930
• Fuentes F, Alcala-Diaz JF, Watts GF, Alonso R, Muniz O, Diaz-Diaz JL, Mata N, Sanchez Munoz-Torrero JF, Brea A, Galiana J, Figueras R, Aguado R, Piedecausa M, Cepeda JM, Vidal JI, Rodriguez-Cantalejo F, Lopez-Miranda J, Mata P; SAFEHEART Investigators. Statins do not increase the risk of developing type 2 diabetes in familial hypercholesterolemia: The SAFEHEART study. Int J Cardiol. 2015 Dec 15;20 PMID 26296047
• Alonso R, Andres E, Mata N, Fuentes-Jimenez F, Badimon L, Lopez-Miranda J, Padro T, Muniz O, Diaz-Diaz JL, Mauri M, Ordovas JM, Mata P; SAFEHEART Investigators. Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. J Am Coll Cardiol. 2014 May 20;63(19):1982-9. doi: 10.1016/j.jacc.2014.01.063. Epub PMID 24632281
• Alonso R, Mata P, Zambon D, Mata N, Fuentes-Jimenez F. Early diagnosis and treatment of familial hypercholesterolemia: improving patient outcomes. Expert Rev Cardiovasc Ther. 2013 Mar;11(3):327-42. doi: 10.1586/erc.13.7. PMID 23469913
• Aledo R, Alonso R, Mata P, Llorente-Cortes V, Padro T, Badimon L. LRP1 gene polymorphisms are associated with premature risk of cardiovascular disease in patients with familial hypercholesterolemia. Rev Esp Cardiol (Engl Ed). 2012 Sep;65(9):807-12. doi: 10.1016/j.recesp.2012.03.013. Epub 2012 Jul 20. English, Spanish. PMID 22819221
• Vazquez C, Alonso R, Garriga M, de Cos A, de la Cruz JJ, Fuentes-Jimenez F, Salas-Salvado J, Mata P. Validation of a food frequency questionnaire in Spanish patients with familial hypercholesterolaemia. Nutr Metab Cardiovasc Dis. 2012 Oct;22(10):836-42. doi: 10.1016/j.numecd.2011.01.007. Epub 2011 Jun 23. PMID 21703832
• Mata N, Alonso R, Badimon L, Padro T, Fuentes F, Muniz O, Perez-Jimenez F, Lopez-Miranda J, Diaz JL, Vidal JI, Barba A, Piedecausa M, Sanchez JF, Irigoyen L, Guallar E, Ordovas JM, Mata P. Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART). Lipids Health Dis. 2011 Jun 10;10:94. doi: 10.1186/1476-51 PMID 21663647
• Criado-Garcia J, Fuentes F, Cruz-Teno C, Garcia-Rios A, Jimenez-Morales A, Delgado-Lista J, Mata P, Alonso R, Lopez-Miranda J, Perez-Jimenez F; Spanish Group for the Study of Familiar Hypercholesterolemia. R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study. Lipids Health Dis. 2011 Apr 9;10:50. doi: 10.1186/1476-511X PMID 21477332

Идентификаторы

NCT: NCT02693548 · SAFEHEART

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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