Sickle cell disease (SCD) is the most common monogenic disorder worldwide and is now recognized as a systemic cardiovascular disease associated with chronic hemolysis, endothelial dysfunction, and progressive vasculopathy. Despite improved survival, patients exhibit early cardiovascular complications, reduced exercise capacity, and major impairment in quality of life (QoL). Sedentary behavior is highly prevalent, contributing to deconditioning, increased cardiovascular risk, and psychosocial burden. Although moderate physical activity is safe when supervised, no structured cardiovascular rehabilitation program currently exists for young SCD patients in France.

To evaluate at 12 months the impact of a cardiovascular rehabilitation program compared with standard care on health-related QoL in children, adolescents, and young adults aged 8–25 years with SCD.

Multicenter, randomized, controlled, open-label trial with two parallel groups ( n = 228; 114 per group). Participants aged 8–25 years with SCD will be followed for 12 months; recruitment period is 24 months, total study duration 36 months. Primary endpoint: change in PedsQL™ 4.0 score between baseline and 12 months. Secondary outcomes include VO _2max , ventilatory parameters, muscle strength, physical activity, echocardiographic parameters, clinical specific evolution, pain scores, mental health and disease knowledge. The intervention group will undergo a 12-week hybrid rehabilitation program combining supervised exercise training and therapeutic education, delivered in-center and at home with digital support. All patients will receive standard care with assessments at baseline and 12 months; analyses will follow intention-to-treat and per-protocol approaches.

The program is expected to improve quality of life, aerobic capacity, and physical activity level, while reducing sedentary behavior and global cardiovascular risk. It may also enhance disease knowledge, psychosocial integration, and patient autonomy. A reduction in hospitalizations and healthcare utilization is anticipated.

Cardiovascular rehabilitation represents a promising strategy targeting the combined burden of vasculopathy, deconditioning, and sedentary lifestyle in SCD. This programme could optimize long-term outcomes and provide both individual clinical benefits and broader socio-economic impact.