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.
Abstract
Introduction: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low density lipoprotein cholesterol (LDLc) levels, increasing early cardiovascular risk. Many patients do not reach LDLc 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 subclinical 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 analysis: For 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 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.
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A., V. J., P., G., J., M. M., A., D. C., B., S., A., O. P., L., Q. J., P., G. M., E., M. R., C., G. S., A., B. R., A., H. M., R., S. S., E., B. G. M., Y., G. R., A., R. M., A., C. R., J., L. R. B. A., G., L. M., R., R. L., R., P. B., V., L. E., S., L. V. M. d., F., R. A., J., B. R., F., A. M. I., A., M. R. J., L., F. A. M., Lopez,, S. (2025). 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.. arXiv preprint arXiv:10.64898/2025.12.22.25342692.
Vargas-Hitos, J. A., Gonzalez-Bustos, P., Martin-Jaimez, M. J., Diaz Chamorro, A., Sanchez-Checa, B., Ortiz Parra, A., Quesada Jimenez, L., Garcia Mateo, P., Martinez Rosales, E., Garcia Sanchez, C., Baena Raya, A., Hernandez Martinez, A., Sanchez Sanchez, R., Bellon Guardian, M. E., Garcia Rivero, Y., Roman Munoz, A., Contreras Rodriguez, A., Lainez Ramos Bossini, A. J., Lopez Milena, G., Rivera Lopez, R., Penafiel Burkhardt, R., Lopez Espinosa, V., Lopez Velez, M. d. S., Rodriguez Aleman, F., Blanco Ramos, J., Aomar Millan, I. F., Montes Romero, J. A., Fernandez Almira, M. L., and Sanchez Lopez,. "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.." arXiv preprint arXiv:10.64898/2025.12.22.25342692 (2025).