Exploring Muscular Senescence in Transfusion-Dependent Thalassemia without Cardiac Iron Overload: Roles of FGF21, ICAM1 and Post-Exercise Pulmonary Congestion

β-thalassemia (β-thal) is a widespread monogenic disorder characterized by chronic hemolytic anemia, managed with transfusions and iron chelation therapy. Previous studies have reported that transfusion-dependent β-thalassemic (TDT) patients show reduced exercise capacity, which has been related to anemia, iron overload cardiomyopathy, and possible muscular deconditioning. Of note sarcopenia and reduced body mass index (BMI) has been recently described in patients with TDT (Thavonun S et al 2023). Here, we evaluated 9 TDT patients without cardiac iron overload on MRI, matched for age (40.4±7.9 y), sex (4 F; 5 M), and normal BMI (22.4±2.9 Kg/m²) with 9 healthy controls (age 37.9±12.2 y; BMI 22.9±3.9 Kg/m²). Handgrip strength was assessed in all subjects, and bioelectrical impedance analysis (BIA) was used to evaluate fat and lean body mass (LBM). Since post-exercise lung ultrasonography (LUS) reliably assesses extravascular lung water and is a prognostic tool in heart failure (Simonovic D et al 2021), we evaluated subclinical parameters of systolic and diastolic dysfunction using transthoracic echocardiography at rest. We also analyzed serum ICAM-1 and FGF21 respectively as markers of vascular endothelial activation, and myocyte dysfunction (Jin L. et al 2022). ELISA for ICAM1 and FGF21 was carried out before and after cardiopulmonary exercise testing (CPET), along with pulmonary B-lines assessed by ultrasound. Resting echocardiographic examination did not show significant difference in cardiac output between the two groups nor of the main systolic and diastolic parameters. At exercise testing, TDT patients had significantly lower oxygen consumption values than healthy controls at both anaerobic threshold (p<0.001) and maximal effort (p<0.001). Chronotropic response (HR) to exercise and maximal O2 pulse were significantly lower in TDT patients (p<0.05 and p<0.001 respectively). BIA revealed lower LBM in TDT (p<0.005). Similarly, they showed lower Handgrip strength (p<0.05) when compared to healthy subjects. No pulmonary or ventilatory alterations were found during exertion, but there was a significant increase in B-lines at peak exercise (p<0.05) again only in TDT patients. We found significantly increased serum levels of FGF-21 in TDT patients both at rest (p<0.05) and after CPET (p<0.001) when compared to healthy subjects. Post-exercise ICAM-1 levels were also significantly higher (p<0.005) than in healthy individuals. ICAM1 and FGF21 and their response to maximal exercise correlate with LBM, Handgrip strength, post exercise B-lines and CPET parameters Our study shows for the first time that TDT patients in the absence of cardiac iron overload exhibit clinical and biological responses to physical exercise similar to those observed in conditions with high cardiovascular risk such as metabolic syndrome (Carvalho LP et al 2018; Vecchiatto B et al 2022). The increased ICAM-1 and FGF21 in response to exercise indicate the presence of inflammatory vasculopathy and of early myocyte senescence. Taken together our data support soluble FGF21 and LUS as novel markers of early cardiovascular involvement and precocious muscle senescent in TDT patients without cardiac iron overload and normal BMI.