Unraveling the Potential of Physical Activity and High-Intensity Interval Training in the Treatment of Familial Hypercholesterolemia: Impact on Cardiorespiratory Fitness, Atherosclerosis, and Underlying Mechanisms. Study protocol of the UPPA-FH Project.

IntroductionFamilial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein -cholesterol (LDL-c) levels, increasing early cardiovascular risk. Many patients do not reach LDL-c targets despite treatment. Physical activity and exercise may help by improving cardiorespiratory fitness (CRF), reducing inflammation, and modulating metabolic pathways. This study aims 1) to cross-sectionally evaluate the association of physical activity and CRF with markers of sub-clinical atherosclerosis and a nuclear magnetic resonance-derived metabolomic profile in patients with FH, and 2) to assess the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on CRF (primary outcome), markers of subclinical atherosclerosis, serum biomarkers and metabolomic profiles (secondary outcomes), and to unravel the underlying mechanisms. Methods and analysisFor aim 1, a cross-sectional study will be conducted in approximately 200 patients with FH from Granada and Almeria (Spain). Assessments will include accelerometer-measured physical activity, CRF, markers of subclinical atherosclerosis and metabolomic profiles. For aim 2, a 16-week, parallel-group randomized controlled trial will be conducted with 75 participants assigned to one of three groups: HIIT (4 intervals of 4 minutes at 85-95% of maximal heart rate, 3 days/week), MICT (34 minutes at 69-76% of maximal heart rate, 3 days/week) or usual care. CRF will be assessed using the modified Bruce test. Markers of subclinical atherosclerosis will include vascular inflammation (PET/CT scan), arterial stiffness (Mobil-O-Graph(R) 24h pulse wave monitor), carotid intima-media thickness, and carotid plaque presence (carotid Doppler ultrasound). Metabolomic profiles will be analyzed using nuclear magnetic resonance spectroscopy. Analyses will include correlation and regression models for cross-sectional associations, and linear mixed-effects models for RCT outcomes, following an intention-to-treat approach with additional sensitivity analyses. Ethics and disseminationThe study was approved by the Ethics Committee for Biomedical Research of Granada (ref. 1417-N-23), and findings will be disseminated through peer-reviewed publications, conference presentations, and outreach activities aimed at patients and healthcare professionals. Trial registration numberClinicalTrials.gov ID NCT06833944. Strengths and limitations of this studyO_LIThis is the first study to evaluate the effects of structured exercise in patients with familial hypercholesterolemia, comparing two exercise modalities (high-intensity interval training and moderate-intensity continuous training) and assessing multiple clinically relevant health outcomes (cardiorespiratory fitness, subclinical atherosclerosis, and metabolomic profiles). C_LIO_LIThe study integrates objective measures of physical activity (accelerometry), cardiorespiratory fitness (VO{square}max), vascular imaging (PET/CT, carotid ultrasound, arterial stiffness), and metabolomics, providing a comprehensive assessment of both functional and mechanistic outcomes. C_LIO_LIThe interventions are supervised, individualized, and follow established exercise reporting guidelines (CERT), which enhances safety, adherence, and reproducibility. C_LIO_LIThe intervention duration (16 weeks) and the specific clinical population (aged 18- 70 years, clinically stable, without cardiovascular disease) may limit assessment of long-term effects and generalizability to all patients with familial hypercholesterolemia. C_LIO_LIAlthough some outcomes are directly applicable to clinical or exercise practice, other mechanistic outcomes (PET/CT, metabolomics, and vascular imaging) provide rigorous scientific insight but have lower direct applicability. C_LI