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This multicenter, non-randomized interventional study aims to assess coronary artery disease progression over 5 years in patients with genetically confirmed heterozygous familial hypercholesterolemia (HeFH), using coronary computed tomography angiography (CCTA).
The primary endpoint is the visual evaluation of coronary stenosis using CAD-RADS v2.0, identifying changes between baseline (2018-2022) and study inclusion. The study will enroll 300 patients (100 protected, 200 non-protected) from La Pitié-Salpêtrière hospital and Saint Antoine Hospital (Paris). Participation lasts up to one week. Total study duration is 2 years, with extended follow-up through routine care data over 10 years.
HeFH is an autosomal dominant genetic disorder characterized by lifelong elevated LDL-C levels, which significantly increase the risk of premature coronary atherosclerosis. Cardiovascular risk stratification in HeFH remains challenging due to limitations of traditional risk scores and stress testing. The coronary artery calcium (CAC) score is a useful tool for reclassifying cardiovascular risk but fails to detect non-calcified plaques, which may be prevalent in HeFH despite a CAC score of zero. Previous studies suggest a prevalence of non-calcified plaques as high as 30% in molecularly diagnosed HeFH patients.
This multicenter interventional, non-randomized comparative study aims to evaluate the progression of coronary artery disease over a 5-year period in patients with genetically confirmed heterozygous familial hypercholesterolemia (HeFH). Using coronary computed tomography angiography (CCTA), the study will assess both calcified and non-calcified plaque burden in this high-risk population.
The primary outcome is the visual, semi-quantitative evaluation of coronary stenosis severity using CAD-RADS v2.0 classification to identify high-risk plaques and categorize patients as having regression, stability, or progression of coronary disease based on changes in CAD-RADS categories between baseline (2018-2022) and the DESTINY-FH study visit.
The study will enroll 300 patients (100 "protected" and 200 "non-protected") from La Pitié-Salpêtrière hospital and Saint Antoine Hospital (Paris). Individual participation will last from one day to one week. Total study duration is 2 years, with additional 10-year follow-up using routinely collected medical records.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients with protected and unprotected familial hypercholesterolemia | Other | Coronary computed tomography angiography with injection of iodinated contrast material |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Coronary computed tomography angiography | Other | Coronary computed tomography angiography with injection of iodinated contrast material |
|
| Measure | Description | Time Frame |
|---|---|---|
| Progression of coronary artery disease over 5 years in patients with heterozygous familial hypercholesterolemia | 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 | 1 day |
| Measure | Description | Time Frame |
|---|---|---|
| Change in total coronary plaque volume, lesion type, and proximal aortic calcifications. | 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 |
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Inclusion Criteria:
Exclusion Criteria:
Patient under guardianship, or unable to give consent
Pregnancy, breast-feeding
Technical contraindication: weight > 250 kg
Simultaneous participation in other interventional research involving the human body, or period of exclusion following previous research involving the human body still in progress.
Adults subject to a legal protection order
Contraindication to esmolol and/or atenolol
Only for patients who need to undergo a CT angiogram and a thoraco-abdominal-pelvic CT scan:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Antonio GALLO, MD, PhD | Contact | 33(0)1 42 17 57 74 | antonio.gallo@aphp.fr | |
| Franck BOCCARA, MD, PhD | Contact | 33(0)1 49 28 24 49 | franck.boccara@aphp.fr |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Plateau d'investigation clinique (PIC) IHU-ICAN | Not yet recruiting | Paris | 75013 | France |
Data are available upon reasonable request The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients. Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations
Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
Researchers who provide a methodologically sound proposal
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| ID | Term |
|---|---|
| D003324 | Coronary Artery Disease |
| D050197 | Atherosclerosis |
| ID | Term |
|---|---|
| D003327 | Coronary Disease |
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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Biology:
Specific omic biology (including metabolomics, lipidomics, proteomics, genetics, inflammation, and metagenomics).
Imaging:
Coronary computed tomography angiography with injection of iodinated contrast material DEXA scan Fibroscan Non-invasive vascular assessment of the fundus using adaptive optics
Other:
Measurement of arterial stiffness Injection of esmolol or atenolol only for patients with a heart rate >65 bpm.
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| 1 day |
| Survival curve of major cardiovascular events incidence. | Incidence of myocardial infarction, ischemic stroke, transient ischemic attack, and coronary, carotid, and/or femoral revascularization since baseline CCTA in both groups | 1 day |
| Cox regression analysis of cardiovascular event occurrence and associated clinical, biological, and omics data. | 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. | 1 day |
| Linear regression of clinical and biological variables by CAD-RADS category change. | 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. | 1 day |
| Comparison of omics data by plaque volume change and CAD-RADS category shift. | 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. | 1 day |
| Baseline prevalence of carotid plaque 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 | 1 day |
| Baseline prevalence of femoral plaque by group | 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 | 1 day |
| Baseline aortic valve calcium score by group | 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) | 1 day |
| Baseline thoracic aorta calcium score by group | 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) | 1 day |
| Baseline diameters of the ascending and descending aorta by group | 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). | 1 day |
| Correlation between baseline carotid plaque presence and change in coronary plaque volume | 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) | Baseline to 5 years |
| Correlation between baseline femoral plaque presence and change in coronary plaque volume | 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) | Baseline to 5 years |
| Correlation between baseline CAC score (aortic valve and thoracic aorta) and coronary plaque progression | 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. | 1 day |
| Correlation between baseline aortic diameters and coronary plaque progression | 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). | 1 day |
| Baseline epicardial fat volume by group | 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) | 1 day |
| Baseline epicardial fat density by group | 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) | 1 day |
| Baseline subdiaphragmatic abdominal adipose tissue volume at L1 by group | 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 (%) | 1 day |
| Baseline subdiaphragmatic abdominal adipose tissue density at L1 by group | 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) | 1 day |
| Baseline arterial wall thickness by group | 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). | 1 day |
| Baseline arterial lumen diameter by group | 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). | 1 day |
| Baseline arterial wall-to-lumen ratio by group | 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). | 1 day |
| Baseline arterial wall cross-sectional area by group | 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). | 1 day |
| Correlation between retinal arterial wall thickness and coronary plaque progression | 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 | 1 day |
| Correlation between retinal lumen diameter and coronary plaque progression | 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. | 1 day |
| Correlation between retinal wall-to-lumen ratio and coronary plaque progression | 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 | 1 day |
| Correlation between retinal arterial wall cross-sectional area and coronary plaque progression | 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 | 1 day |
| Comparison of liver and spleen density at baseline between groups | Comparison of unenhanced liver and spleen density between groups at baseline. | 1 day |
| Gut microbiota composition at baseline using metabolomics and metagenomics. | 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. | 1 day |
| Association between baseline omics data and coronary plaque progression. | 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. | 1 day |
| Change in gut microbiota composition between baseline and inclusion | Comparison of gut microbiota composition between baseline (for patients previously included in the FHCALC study) and inclusion, in both groups | 1 day |
| Comparison of arterial stiffness at baseline between groups. | Comparison of arterial stiffness measurements between groups at baseline. | 1 day |
| SF-36 Health Survey score at inclusion | 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) | 1 day |
| Seattle Angina Questionnaire-7 (SAQ-7) score at inclusion | 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) | 1 day |
| Rose Dyspnea Scale score at inclusion | 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) | 1 day |
| Patient Health Questionnaire-2 (PHQ-2) score at inclusion | 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) | 1 day |
| Hospital Anxiety and Depression Scale (HADS) score at inclusion | 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 | 1 day |
| CONSTANCES study questionnaire scores at inclusion | 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 | 1 day |
| Incidence of major cardiovascular events at 5 and 10 years | 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. | 5 and 10 years |
| APHP- Hospital Saint-Antoine | Not yet recruiting | Paris | Île-de-France Region | 75013 | France |
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| APHP-Sorbonne, Pitié Salpêtrière Hospital | Recruiting | Paris | Île-de-France Region | 75013 | France |
|
| D001161 |
| Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |