NMES-Facilitated Mandibular Rehabilitation for Spasticity-Related Trismus in ALS.

Transfusion dependent thalassemia (TDT) is a worldwide distributed hereditary red cell disorder. The main clinical manifestations are chronic hemolytic anemia and ineffective erythropoiesis both link to oxidation and abnormal iron homeostasis [, ]. Chronic transfusion regimen requires a personalized iron chelation therapy to effectively reduce iron burden []. The cytotoxic organ iron accumulation might contribute to organ damage, resulting in liver and heart disease. Patients’ quality of life is deeply affected by fatigue and muscle weakness which generally appears before heart iron-overload and might be related the cumulative effect of different factors such as muscle waste-associated decrease muscle strength, osteoporosis, vitamin D deficiency and chronic anemia [–]. Up to now there is a lack of knowledge on muscular performance and early cardiovascular disease in TDT patients beyond cardiac iron overload, with particular regard to how nutritional status and skeletal muscle phenotype contribute to exercise intolerance. Of note, Pennell et al. reported that TDT patients develop an adaptive cardiac physiology, which can lead to increasing cardiac output to maintain oxygen delivery, in absence of cardiac iron loading []. Indeed, recent evidence indicates that pathological heart remodeling and myocardial dysfunction might appear before heart iron overload in both mouse model and patients with TDT [, ]. Myocardial fibrosis and iron-induced electrical conduction disturbances can lead to arrhythmias []. and altered chronotropic response to exercise [, ]. Previous studies have shown that TDT patients have reduced cardiovascular fitness and exercise capacity in terms of maximum oxygen consumption (VOmax), which has been related to anemia, iron overload cardiomyopathy, and possible muscular deconditioning, however, the extent and clinical characterization of early muscle-nutritional impairment (e.g., lean mass, strength and physical activity) and its relationship with exercise-induced cardiovascular abnormalities in TDT remains insufficiently defined [–]. Sarcopenia and low body mass index are also reported [–]. Identifying early functional changes before structural cardiomyopathy develops remains a clinical challenge. Recent evidence highlights the prognostic capability of lung ultrasound combined with exercise testing in heart failure with preserved ejection fraction (HFpEF) []. In addition, B-lines is emerging as excellent surrogate for pulmonary capillary wedge pressure (PCWP) and diastolic dysfunction with HFpEF triggered by exercise testing []. This might be corroborated by soluble markers of pro-inflammatory and shear stress vascular response to exercise such as intercellular adhesion molecule-1 (ICAM-1) []. Indeed, increased circulating ICAM-1 has been associated with atherosclerosis [], myocardial infarction, heart failure and inflammatory cardiomyopathies []. In addition, Vinchi et al. have recently described increased markers of inflammatory vasculopathy in TDT patients, reaching values similar to those described in individuals with sickle cell disease []. Inflammatory vasculopathy might be a still an under-recognized factor in the pathogenesis of TDT related myocardial dysfunction. This is extremely interesting since mild chronic inflammation has been also related to cardiometabolic disease []. Although ICAM-1 is not a unique marker of inflammation, its up-regulation mirrors chronic vascular stress that may compromise skeletal-muscle perfusion and contribute to functional deconditioning and possible senescence [–]. Of note, increased ICAM-1 expression is also linked to physical frailty and sarcopenia [].