Atrial fibrillation in ß-thalassemia Major Patients: Diagnosis, Management and Therapeutic Options.

The prevalence of atrial fibrillation (AFib) in ß-thalassemia major (ß-TM) patients has increased in the last few years, reaching up to 33.0%. Several factors may drive this value to even more in the next few years. We summarized the main challenges in the management and therapy of AFib in this very specific group of patients.

Exploring New Drug Repurposing Opportunities for MEK Inhibitors in RASopathies: A Comprehensive Review of Safety, Efficacy, and Future Perspectives of Trametinib and Selumetinib.

The RASopathies are a group of syndromes caused by genetic variants that affect the RAS-MAPK signaling pathway, which is essential for cell response to diverse stimuli. These variants functionally converge towards the overactivation of the pathway, leading to various constitutional and mosaic conditions. These syndromes show overlapping though distinct clinical presentations and share congenital heart defects, hypertrophic cardiomyopathy (HCM), and lymphatic dysplasia as major clinical features, with highly variable prevalence and severity. Available treatments have mainly been directed to target the symptoms. However, repurposing MEK inhibitors (MEKis), which were originally developed for cancer treatment, to target evolutive aspects occurring in these disorders is a promising option. Animal models have shown encouraging results in treating various RASopathy manifestations, including HCM and lymphatic abnormalities. Clinical reports have also provided first evidence supporting the effectiveness of MEKi, especially trametinib, in treating life-threatening conditions associated with these disorders. Nevertheless, despite notable improvements, there are adverse events that occur, necessitating careful monitoring. Moreover, there is evidence indicating that multiple pathways can contribute to these disorders, indicating a current need to more accurate understand of the underlying mechanism of the disease to apply an effective targeted therapy. In conclusion, while MEKi holds promise in managing life-threatening complications of RASopathies, dedicated clinical trials are required to establish standardized treatment protocols tailored to take into account the individual needs of each patient and favor a personalized treatment.

Defining the variant-phenotype correlation in patients affected by Noonan syndrome with the RAF1:c.770C>T p.(Ser257Leu) variant.

Hypertrophic cardiomyopathy (HCM) is the major contributor to morbidity and mortality in Noonan syndrome (NS). Gain-of-function variants in RAF1 are associated with high prevalence of HCM. Among these, NM_002880.4:c.770C > T, NP_002871.1:p.(Ser257Leu) accounts for approximately half of cases and has been reported as associated with a particularly severe outcome. Nevertheless, comprehensive studies on cases harboring this variant are missing. To precisely define the phenotype associated to the RAF1:c.770C > T, variant, an observational retrospective analysis on patients carrying the c.770C > T variant was conducted merging 17 unpublished patients and literature-derived ones. Data regarding prenatal findings, clinical features and cardiac phenotypes were collected to provide an exhaustive description of the associated phenotype. Clinical information was collected in 107 patients. Among them, 92% had HCM, mostly diagnosed within the first year of life. Thirty percent of patients were preterm and 47% of the newborns was admitted in a neonatal intensive care unit, mainly due to respiratory complications of HCM and/or pulmonary arterial hypertension. Mortality rate was 13%, mainly secondary to HCM-related complications (62%) at the average age of 7.5 months. Short stature had a prevalence of 91%, while seizures and ID of 6% and 12%, respectively. Two cases out of 75 (3%) developed neoplasms. In conclusion, patients with the RAF1:c.770C > T pathogenic variant show a particularly severe phenotype characterized by rapidly progressive neonatal HCM and high mortality rate suggesting the necessity of careful monitoring and early intervention to prevent or slow down the progression of HCM.

Myocardial longitudinal strain as the first herald of cardiac impairment in very early iron overload state: an echocardiography and biosusceptometry study on beta-thalassemia patients.

BACKGROUND: Heart diseases due to iron overload are still the main cause of mortality in patients affected by beta-thalassemia. Detection of cardiac iron overload in pre-clinical stage allows tailoring of chelation therapy and follow-up strategies. Echocardiographic longitudinal strain analysis may be a useful tool for early detection of cardiac functional impairment iron-related. METHODS: We examined 58 patients with beta-thalassemia on regular blood transfusion and iron chelation, without overt cardiac disease who had recent Biosusceptometry SQUID to quantify liver iron concentration and cardiac assessment by CMR T2*. RESULTS: Average global longitudinal strain (GLS) was able to identify abnormal (<20 ms) cardiac T2* values with 96% specificity and negative predictive value of 92% (AUC 0.84, P=0.01). Apical 4-ch GLS may help identify early longitudinal impairment associated with severe liver iron overload with 96% specificity and negative predictive value of 92% (AUC 0.84, P=0.02). Patients with severe liver iron overload had lower average Global Longitudinal Strain values compared to other patients (P-value =0.005). CONCLUSION: GLS was a sensitive marker to detect both myocardial and liver iron overload in a population that is still free from cardiac symptoms. Thus, strain echocardiography may be a useful tool for early detection of iron overload in Beta-thalassemia.