"Detection and Follow-up of Coronary Lesions in HeFH (DESTINY-FH Study)"

The evolution of coronary artery disease will be assessed over 5 years in patients with heterozygous familial hypercholesterolemia using coronary CT angiography (CTA). The number of patients with regression, stability, or progression of coronary stenosis will be determined using semi-quantitative visual assessment of coronary stenoses according to the CAD-RADS v2.0 classification, including visual characterization of high-risk plaque features.Time Frame: 5 years Unit of Measure: Number and percentage of participants with regression, stability, or progression of coronary stenosis

Assessment of coronary artery disease progression in HeFH patients using 5-years follow-up CCTA. CAD-RADS v2.0 will be used to evaluate changes in stenosis severity and identify high-risk plaques. Progression will be defined by a change in CAD-RADS category between first CCTA (defined as baseline, realized between 2018 and 2022) and inclusion in DESTINY-FH

Incidence of myocardial infarction, ischemic stroke, transient ischemic attack, and coronary, carotid, and/or femoral revascularization since baseline CCTA in both groups

Evaluation of the association between cardiovascular event occurrence (as defined in outcome 2) and clinical, biological, omics, and macro/microvascular data using Cox regression analysis.

Comparison and linear regression of clinical and biological explanatory variables according to change in CAD-RADS category between baseline and inclusion, in the overall cohort and stratified by groups.

Comparison of omics data based on the quantitative change in total coronary plaque volume or change in CAD-RADS category between baseline and inclusion, stratified by group.

Presence or absence of carotid plaque will be assessed at baseline using coronary CT angiography (CTA). Prevalence of carotid plaque will be compared between groups at baseline.

Unit of Measure:

% of participants with carotid plaque

Presence or absence of femoral plaque will be assessed at baseline using duplex Doppler ultrasound. Prevalence of femoral plaque will be compared between groups at baseline.

Unit of Measure:% of participants with femoral plaque

Aortic valve calcium score will be measured at baseline using non-contrast cardiac CT according to the Agatston method. Scores will be compared between groups at baseline.

Unit of Measure:Agatston score (Agatston units)

Thoracic aorta calcium score will be measured at baseline using non-contrast cardiac CT according to the Agatston method. Scores will be compared between groups at baseline.

Unit of Measure:Agatston score (Agatston units)

Aortic diameters will be measured at baseline using CT angiography (mm). Measurements will be compared between groups at baseline. Unit of Measure: Aortic diameter (mm).

Presence or absence of carotid plaque will be assessed at baseline using duplex Doppler ultrasound. Its correlation with change in total coronary plaque volume between baseline and follow-up will be evaluated. Coronary plaque volume will be quantified using coronary CT angiography (CTA).

Unit of Measure:Change in coronary plaque volume (mm³)

Presence or absence of femoral plaque will be assessed at baseline using duplex Doppler ultrasound. Its correlation with change in total coronary plaque volume between baseline and follow-up will be evaluated. Coronary plaque volume will be quantified using coronary CT angiography (CTA).

Unit of Measure:

Change in coronary plaque volume (mm³)

Coronary artery calcium (CAC) score will be measured at baseline using non-contrast CT (Agatston method). The CAC score of the aortic valve and thoracic aorta will be correlated with change in total coronary plaque volume (mm³) and CAD-RADS category between baseline and follow-up, as assessed by CTA.

Unit of Measure: CAC score (Agatston units); change in coronary plaque volume (mm³); change in CAD-RADS category.

Aortic diameters (ascending and thoracic aorta) will be measured at baseline using CT angiography (mm). Aortic diameter values will be correlated with change in total coronary plaque volume (mm³) and plaque vulnerability features on coronary CTA between baseline and follow-up.

Unit of Measure: Aortic diameter (mm); change in coronary plaque volume (mm³).

Epicardial fat volume will be measured at baseline using coronary CT angiography (CTA). Volumes will be compared between groups at baseline.

Unit of Measure: Epicardial fat volume (cm³)

Epicardial fat density will be measured at baseline using coronary CT angiography (CTA). Density will be compared between groups at baseline.

Unit of Measure: Epicardial fat density (Hounsfield Units, HU)

Subdiaphragmatic abdominal adipose tissue volume will be quantified at the level of the first lumbar vertebra (L1) using non-contrast CT. Segmentation will be performed using standard attenuation thresholds for adipose tissue. Relative adipose tissue volume will be compared between groups at baseline.

Unit of Measure:Relative adipose tissue volume (%)

Mean attenuation of subdiaphragmatic abdominal adipose tissue will be measured at the level of L1 using non-contrast CT. Mean density will be compared between groups at baseline.

Unit of Measure:Mean adipose tissue density (Hounsfield Units, HU)

Arterial wall thickness will be measured at baseline using adaptive optics retinal imaging. Values will be compared between groups at baseline.

Unit of Measure: Wall thickness (µm).

Arterial lumen diameter will be measured at baseline using adaptive optics retinal imaging. Values will be compared between groups at baseline.

Unit of Measure: Lumen diameter (µm).

Wall-to-lumen ratio will be calculated at baseline using adaptive optics retinal imaging. Ratios will be compared between groups at baseline.

Unit of Measure: Wall-to-lumen ratio (unitless).

Arterial wall cross-sectional area will be measured at baseline using adaptive optics retinal imaging. Values will be compared between groups at baseline.

Unit of Measure: wall cross-sectional area (µm²).

Arterial wall thickness will be measured at baseline using adaptive optics retinal imaging. Its correlation with change in total coronary plaque volume (mm³) and CAD-RADS category between baseline and follow-up will be evaluated.Unit of Measure: Wall thickness (µm); change in coronary plaque volume (mm³); CAD-RADS category

Arterial lumen diameter will be measured at baseline using adaptive optics retinal imaging. Its correlation with change in total coronary plaque volume (mm³) and CAD-RADS category between baseline and follow-up will be evaluated.

Unit of Measure: Lumen diameter (µm); change in coronary plaque volume (mm³); CAD-RADS category.

Wall-to-lumen ratio will be measured at baseline using adaptive optics retinal imaging. Its correlation with change in total coronary plaque volume (mm³) and CAD-RADS category between baseline and follow-up will be evaluated.

Unit of Measure: Wall-to-lumen ratio (unitless); change in coronary plaque volume (mm³); CAD-RADS category

Arterial wall cross-sectional area will be measured at baseline using adaptive optics retinal imaging. Its correlation with change in total coronary plaque volume (mm³) and CAD-RADS category between baseline and follow-up will be evaluated.

Unit of Measure: Cross-sectional area (mm²); change in coronary plaque volume (mm³); CAD-RADS category

Comparison of unenhanced liver and spleen density between groups at baseline.

Characterization of gut microbiota at baseline in both groups using targeted and untargeted metabolomics (e.g., secondary bile acids, choline/tryptophan/cholesterol derivatives, short-chain fatty acids) and metagenomic sequencing with bioinformatic analysis of bacterial populations.

Comparison of baseline omics data according to the change in total coronary plaque volume or CAD-RADS category between baseline and inclusion, stratified by group.

Comparison of gut microbiota composition between baseline (for patients previously included in the FHCALC study) and inclusion, in both groups

Comparison of arterial stiffness measurements between groups at baseline.

The SF-36 Health Survey will be administered at inclusion. The total score and domain scores will be recorded, ranging from 0 to 100, where higher scores indicate better health status.

Unit of Measure: Score (0-100)

The SAQ-7 will be administered at inclusion. Scores range from 0 to 100, with higher scores indicating less angina and better functional status.

Unit of Measure: Score (0-100)

The Rose Dyspnea Scale will be administered at inclusion. Scores range from 0 to 4, where higher scores indicate greater breathlessness.

Unit of Measure: Score (0-4)

The PHQ-2 will be administered at inclusion. Scores range from 0 to 6, with higher scores indicating greater depressive symptoms.

Unit of Measure: Score (0-6)

The HADS will be administered at inclusion. Scores range from 0 to 21 for anxiety and 0 to 21 for depression, with higher scores indicating greater symptom severity.

Unit of Measure: Score (0-21) for anxiety; Score (0-21) for depression

Selected standardized questionnaires from the CONSTANCES cohort study will be administered at inclusion. Scores will be recorded according to the original scoring system of each questionnaire (specific scales and units to be defined).

Unit of Measure: As per original scoring system of each CONSTANCES questionnaire

Occurrence of major cardiovascular events-including myocardial infarction, ischemic stroke, transient ischemic attack (TIA), and coronary, carotid, and/or femoral revascularization-will be recorded. Events will be ascertained through clinical records and patient interviews. Survival curves will be generated to estimate cumulative incidence at both 5- and 10-year follow-up.