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

Detection and Longitudinal Follow-up of Non-calcified and Calcified Coronary Lesions in Heterozygous Familial Hypercholesterolemia (DESTINY-FH)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Heterozygous Familial Hypercholesterolemia (HeFH)
• Intervention / Treatment: Other: Coronary computed tomography angiography

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Antonio GALLO, MD, PhD; Phone Number: 33(0)1 42 17 57 74; Email: antonio.gallo@aphp.fr
• Study Contact Backup: Name: Franck BOCCARA, MD, PhD; Phone Number: 33(0)1 49 28 24 49; Email: franck.boccara@aphp.fr

Study Locations

• France
  • Île-de-France Region
    • Paris, Île-de-France Region, France, 75013
      • APHP- Hospital Saint-Antoine
      • Contact: Franck BOCCARA, MD, PhD; Phone Number: 33(0)1 49 28 24 49; Email: franck.boccara@aphp.fr
      • Principal Investigator: Franck BOCCARA, MD, PhD
    • Paris, Île-de-France Region, France, 75013
      • APHP-Sorbonne, Pitié Salpêtrière Hospital
      • Contact: Antonio GALLO, MD, PhD; Phone Number: 33(0)1 42 17 57 74; Email: antonio.gallo@aphp.fr
      • Principal Investigator: Antonio GALLO, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients with heterozygous familial hypercholesterolemia :

1. Aged between 35 and 60.

2. Having undergone CCTA at least 5 years ago exclusively at the same imaging center (ICT de la Pitié Salpetrière):

   • Included in the FH-CALC study
   • Or as part of care between 2018 and 2022 And
   • For the protected group: absence of coronary stenosis (CADRADS 0)
   • For the unprotected group: presence of coronary stenosis (CADRDADS ≥ 1)
3. Patient asymptomatic for exertional chest pain at the time of CCTA
4. Clinical examination performed
5. Beneficiary of a social protection scheme or entitled person (excluding AME)
6. Patient informed and consent form signed

Exclusion Criteria:

1. Patient under guardianship, or unable to give consent
2. Pregnancy, breast-feeding, women of childbearing age in the absence of effective contraception
3. Technical contraindication: waist > 70 cm, weight > 250 kg
4. Renal insufficiency (LC<60)
5. Unbalanced diabetes when acquiring coronary angioscanner between 2018 and 2022.
6. Personal history of cardiovascular disease and myocardial infarction at the time of CCTA
7. Simultaneous participation in other interventional research involving the human body, or period of exclusion following previous research involving the human body still in progress.
8. Contraindication to iodinated contrast media
9. Contraindication to esmolol and/or atenolol
10. Patient having already had an adverse event (AE) during the acquisition of coronary angioscanner between 2018 and 2022.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patients with protected and unprotected familial hypercholesterolemia; Coronary computed tomography angiography with injection of iodinated contrast material	Other: Coronary computed tomography angiography; Coronary computed tomography angiography with injection of iodinated contrast material

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2035

Study Registration Dates

• First Submitted: August 14, 2025
• First Submitted That Met QC Criteria: February 16, 2026
• First Posted (Actual): February 23, 2026

Study Record Updates

• Last Update Posted (Actual): February 23, 2026
• Last Update Submitted That Met QC Criteria: February 16, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Coronary Artery Disease; Atherosclerosis; Cardiovascular Risk; Cardiovascular Events; Coronary Plaque Vulnerability
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Myocardial Ischemia; Coronary Artery Disease; Atherosclerosis
• Other Study ID Numbers: APHP250574

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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
• IPD Sharing Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No