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On the trail of "bad" cholesterol

MedUni Vienna is leading participant in Lancet study on familial hypercholesterolaemia (FH) in Austria
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(Vienna, 21 October 2021) Within the framework of a registry project initiated by the Austrian Atherosclerosis Society (AAS) that has been running for 5 years to register patients with Familial Hypercholesterolaemia (FH) in Austria, the data collected (with active participation from staff of the Medical University of Vienna) were fed into a global registry network of the European Atherosclerosis Society (EAS) and have recently been published in the renowned journal "The Lancet".

Cardiovascular disease is the most common cause of death in Austria, as well as in other western industrialized countries. It is scientifically proven that LDL cholesterol (LDL-C) is involved in the pathogenesis of atherosclerosis, which underlies the classic cardiovascular clinical endpoints such as myocardial infarction and stroke. Epidemiological studies consistently show a correlation of serum LDL-C with myocardial infarction and cardiovascular death. Studies using Mendelian randomisation have shown that the genetically determined regulation of LDL-C correlates with clinical cardiovascular events, especially the risk of myocardial infarction. This provided evidence of the causal relationship between elevated LDL-C levels and cardiovascular disease.

Familial hypercholesterolaemia
Mutations in the gene for the LDL receptor are responsible for around 75% of all FH cases. The remaining 25% are caused by mutations in the gene for apolipoprotein B (the carrier protein for LDL and thus the main ligand of the LDL receptor), PCSK9, LDL receptor adapter protein (LDLR-AP), as well as mutations in still unknown genes, or are of polygenic origin. The classical form of FH follows an autosomal dominant inheritance, an exception being the rare mutations in the LDLR-AP, which are inherited in an autosomal recessive manner.

With an estimated prevalence of about 1:300 (equivalent to around 30,000 people in Austria) FH is one of the most common monogenic metabolic disorders and is characterised by an elevated level of LDL-C in the serum due to the reduced or defective breakdown of LDL. The resulting events (heart attacks, strokes, etc.) can even lead to deaths in childhood and adolescence in untreated homozygous FH. Unfortunately, FH is seriously underdiagnosed in Austria, as in many other countries.

Given the available prevalence data, combined with our knowledge of the mechanism of development of FH and the curative treatment options for FH that have been available for over 30 years (and recently dramatically improved by the development of new lipid-lowering agents), it is completely incomprehensible why most countries have no, or only incomplete, registry data for FH. This also explains the fact that more than 90% of FH patients in Austria are neither diagnosed nor adequately treated.

Screening for FH and establishing a national registry
In most cases, FH is only diagnosed after the appearance of serious sequelae. However, early treatment with cholesterol-lowering drugs can reduce the risk of cardiovascular disease. By means of cascade screening, starting from an affected index patient, first- and second-degree relatives can be screened and, once diagnosed, can be given early, preventive treatment.

Five years ago, under its then president, Hans Dieplinger, Institute of Genetic Epidemiology, Med Uni Innsbruck, the Austrian Atherosclerosis Society (AAS) therefore started a project in the Vienna, Graz, Innsbruck area to establish cascade screening for FH with the aim of establishing a comprehensive nationwide patient registry. Christoph Binder from MedUni Vienna, the current President of the AAS and Vice-President of the EAS, has been leading the FH Registry Project since 2017. Susanne Greber-Platzer (Department of Pediatrics and Adolescent Medicine at MedUni Vienna), MedUni Vienna cardiologist Walter Speidl (Cardiology) and Yvonne Winhofer-Stöckl (Department of Medicine III) are the center managers responsible for the FH patients to be recruited and included at Vienna University Hospital.

These patients must meet at least two of the inclusion criteria. The inclusion criteria include LDL-C concentration >190 mg/dl, total cholesterol concentration >290 mg/dl, early cardiovascular disease, tendon xanthomas, close relatives with hypercholesterolaemia or early myocardial infarction. After inclusion, patients will be interviewed by study assistants about their family and personal medical histories. It is hoped that, with the patients’ help, it will be possible to identify relatives that are potentially similarly affected. The FH diagnosis is confirmed in the index patient and the relatives screened (on a voluntary basis) by means of genetic analysis. The genes for the LDL receptor, ApoB-100, PCSK9 and LDLR-AP are examined and the patients receive genetic counselling. The study was submitted to the ethics committees in all Austrian provinces for review and was approved.

To date, a total of approximately 1,000 patients diagnosed with FH have been included in the registry. The (anonymised) data collected so far have now been forwarded to the global FH Registry (FHSC) of the European Atherosclerosis Society (EAS) and have just been published (together with data from more than 60,000 included FH patients from 56 countries) in the renowned journal "The Lancet". Key findings were that FH is still diagnosed too late and that patients with earlier diagnosis have fewer cardiovascular complications, and that guideline-compliant target values are hardly achieved with monotherapy.

Service: The Lancet
Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Lancet. 2021 Sep 7:S0140-6736(21)01122-3. doi: 10.1016/S0140-6736(21)01122-3. Online ahead of print. PMID: 34506743

LINK: Austrian Atherosclerosis Society