Exercise reveals precocious-subclinical cardiovascular and muscular dysfunction in transfusion dependent beta-thalassemia (TDT) patients without cardiac iron overload

Background: Transfusion-dependent β-thalassemia (TDT) is characterized by reduced exercise capacity due to chronic hemolytic anemia, iron overload cardiomyopathy, and potential skeletal muscle alterations. Early cardiovascular and muscular dysfunction in the absence of cardiac iron overload remains poorly characterized. Methods: In this exploratory study, 9 TDT patients without cardiac iron overload and with normal body mass index (BMI) were matched with 9 healthy controls. Cardiopulmonary exercise testing combined with lung ultrasound (LUS-CPET) was used to assess exercise-induced lung congestion and diastolic dysfunction. Serum biomarkers of endothelial activation (ICAM-1) and muscle-metabolic function (FGF21, miR-577) were evaluated. Resting echocardiography, handgrip strength, and body composition by bioelectrical impedance analysis (BIA) were also assessed. Results: At rest, cardiac output and diastolic function were comparable between groups. However, during LUS-CPET, TDT patients exhibited significantly lower VO₂max, O₂ pulse, and chronotropic index, along with increased B-lines, consistent with exercise-induced diastolic dysfunction. TDT patients also showed reduced lean body mass and handgrip strength. FGF21 levels were elevated at rest and post-exercise, whereas miR-577 levels were reduced. Post-exercise ICAM-1 levels were significantly higher in TDT patients compared to controls. Conclusions: LUS-CPET may represent a useful non-invasive approach to identify early exercise-induced diastolic dysfunction in TDT patients without cardiac iron overload. Altered FGF21 and miR-577 profiles suggest the presence of metabolic dysregulation associated with early skeletal muscle deconditioning.