Advanced Lipoproptein Profiling and Cardiovascular Risk Stratification in Familial Hypercholesterolemia

Familial hypercholesterolaemia (FH) is a genetic disorder characterised by elevated plasma LDLC levels.

The causal role of low-density lipoprotein cholesterol (LDLC) in the progression of cardiovascular disease (CVD) is indisputable: genetic, epidemiological and interventional trials have unanimously shown that a reduction in LDL-C is associated with a reduced risk of CVD.

Some drawbacks related to the limitations of the analytical methods are slowly surfacing due to the lower LDLC target achieved with the combination of several new treatments. This is mainly due to the fact that LDLC is not a comprehensive marker to stratify cardiovascular risk in subjects with increased levels of other atherogenic lipoproteins.

Direct measurement of the concentration of apolipoproteins involved in cholesterol and triglycerides transportation, may provide more information than the simple measure of the cholesterol contained in these particles. There is an interest in measuring the various players involved in the lipoprotein processing chain. These apolipoproteins are increasingly being considered as possible biomarkers of cardiovascular disease risk.

Indeed, there is increasing evidence that advanced lipoprotein testing methods, such as multiplexed measurements of apolipoprotein panels (ApoA-I, A-II, A-IV, B-100, C-I, C-II, C-III, E), provide more detailed information on the dyslipidaemic profiles of patients compared to conventional lipid testing, finally allowing a better understanding and stratification of subclinical atherosclerosis in these patients.

The main objective of this study is to compare the apolipoprotein profile of patients with FH by comparing those with associated hypertriglyceridemia (hyperTG) to those with isolated hypercholesterolaemia.

Adult subjects with a molecular diagnosis of Familial Hypercholesterolemia, treated by a statin, on primary prevention, asymptomatic for cardiovascular symptoms, will be recruited and stratified according to the presence/absence of hyperTG in a case-control prospective observational study design.

The crucial role of dyslipidaemia, in particular hypercholesterolaemia, in the development of cardiovascular diseases is particularly well documented. The causal role of LDLC in the progression of CVD is indisputable: genetic, epidemiological and interventional trials have unanimously shown that a reduction in LDL-C is associated with a reduced risk of CVD.

Some drawbacks related to the limitations of the analytical methods are slowly surfacing due to the lower LDLC target achieved with the combination of several new treatments. This is mainly due to the fact that LDLC is not a comprehensive marker to stratify cardiovascular risk in subjects with increased levels of other atherogenic lipoproteins.

Familial hypercholesterolaemia (FH) is a genetic disorder characterised by elevated plasma LDLC levels.

Plasma levels of key lipoproteins, including LDLC levels, are major determinants and triggers of vascular endothelial damage; monocyte to macrophage differentiation and foam cell formation, leading to the development of atherosclerotic lesions; premature coronary artery disease (CAD); peripheral arterial disease; and supra-aortic stenosis. The earlier these events occur, the higher the cholesterol level.

A growing body of experimental and clinical evidence suggests that triglyceride-rich lipoproteins (TRL), and in particular remnant particles, contribute to atherogenesis and thus to the progression of cardiovascular disease.

In addition, these lipids such as cholesterol and triglycerides (TG) circulate in blood plasma as lipoproteins, supramolecular assemblies whose structure is provided by specific proteins: apolipoproteins.

Direct measurement of the concentration of atherogenic particles involved in the metabolism of cholesterol and TG could therefore provide more information than simply measuring the cholesterol contained in these particles. There is an interest in measuring the various players involved in the lipoprotein processing chain. These apolipoproteins are increasingly being considered as possible biomarkers of cardiovascular disease risk. Indeed, there is increasing evidence that advanced lipoprotein testing methods, such as multiplexed measurements of apolipoprotein panels (ApoA-I, A-II, A-IV, B-100, C-I, C-II, C-III, E), provide more detailed information on the dyslipidaemic profiles of patients compared to conventional lipid testing, allowing for a better understanding and stratification of subclinical atherosclerosis in these patients.

Primary objective:

To compare the apolipoprotein profile of patients with FH by comparing those with associated hyperTG to those with isolated hypercholesterolaemia.

Secondary objectives:

Compare the subclinical impairment of FH patients with and without hyperTG

* Compare the coronary atherosclerotic burden, assessed by the Calcium Score
* Compare carotid atherosclerotic burden, assessed by echodoppler
* Compare femoral atherosclerotic burden, assessed by echodoppler

Conduct of the research :

The patient will be informed of the study and if agree to participate, additional blood tubes will be collected for the research during the blood sampling carried out as part of the usual care.

Analysis will be performed in collaboration with LNE, the France's national metrology laboratory as part of the European CARDIOMET project.

A biobank and serum library will also be constituted during the study for further and additional analysis.

Two groups of patients will be enrolled :

* patients with familial hypercholesterolaemia (FH) and hypertriglyceridemia (hyperTG)
* patients with familial hypercholesterolaemia (FH) without hypertriglyceridemia (hyperTG)

Eligibility Criteria:
Inclusion Criteria:

A. Patients with familial hypercholesterolemia (FH) and with hyperTG :

1. Age \> 18 years
2. Molecular or clinical diagnosis of FH
3. Primary prevention (no coronary artery disease, cerebrovascular disease or lower limb arterial disease)
4. HyperTG or TG levels between 135-500 mg/dl on statin therapy
5. Patient informed of the research, not having objected to participation and having provided written consent for genetic analysis

B. Patients with familial hypercholesterolemia (FH) and without hyperTG :

1. Age \> 18 years
2. Mild diagnosis
3. Primary prevention (no coronary artery disease, cerebrovascular disease or lower limb arterial disease)
4. TG \<135mg/dl on statin therapy
5. Patient informed of the research, did not object to participation and provided written consent for genetic testing

Exclusion Criteria:

1. Secondary prevention or planned coronary intervention or cardiac surgery
2. History of acute or chronic pancreatitis
3. Statin-intolerant patient
4. Glycated haemoglobin level greater than 10.0%.
5. Human Immunodeficiency Virus infection on treatment,
6. Use of corticosteroids
7. Severe renal impairment (Glomerular filtration rate \< 30 ml/min)
8. Pregnant women