Myocardial Fibrosis Occurs in Young Non-Transfusion-Dependent Alpha-Thalassemia Intermedia Patients and Is Related to Anemia and Age in Thalassemia

Introduction

A recent landmark study demonstrated that median pretransfusion hemoglobin in transfusion dependent thalassemia (TDT) >10.5 g/dl has 100% ten-year survival compared to 91% at a hemoglobin of 9.0 with the majority of deaths due to non-iron-related cardiac events (Musallam et al., 2024). Increased anemia-related morbidity and mortality has also been seen in non-transfusion-dependent-thalassemia (NTDT) and low-risk myelodysplastic syndrome suggesting even moderate anemia can have severe consequences to a high oxygen demand organ like the heart (Musallam et al., 2021). Patients with NTDT-α-thalassemia intermedia (TI-α; Hemoglobin H disease and Hemoglobin H-Constant Spring), a presumed benign disorder, have lifelong hemoglobin levels of 8-11 g/dL with most around 8.5 g/dL (Musallam et al., 2024) but very little is known about morbidity and mortality beyond the fifth decade. To address this, we assessed cardiac fibrosis, an accepted predictor of future cardiac dysfunction in TI-α and TDT, using MRI-determined extracellular volume (ECV), with ECV >30% indicating diffuse myocardial fibrosis. We found significant myocardial fibrosis in NTDT-TI-α <40 years old, which was related to degree of anemia and age in patients with thalassemia.

Methods

This study included patients with thalassemia followed at Children’s Hospital Los Angeles who had ECV measured by cardiac MRI. ECV was calculated by T1 mapping pre- and post-gadolinium contrast as previously described. Subjects’ baseline or pretransfusion hemoglobin was determined as median value over 6 months prior to MRI. Data were collected and analyzed using JMP Pro 15.1.0 (SAS Institute Inc., Cary, NC, 2019).

Results

Twenty-two subjects with thalassemia were evaluated: seven with TI-α, four with TI-β, three with E/β-thalassemia, and eight with β-thalassemia major. Subjects' ages ranged from 2 to 63 years at initial evaluation, with median age 27.5 years. All β-thalassemia subjects and three of the TI-α subjects were transfused. Median ECV among all subjects was elevated to 32.4%; median ECV was 32.5% in β-thalassemia and 32.4% among TI-α (p=0.94), ranging 29.7% to 43.7% in NTDT-TI-α. All subjects had normal ejection fraction, no cardiac siderosis, and no symptoms of cardiac disease. ECV increased with decreasing hemoglobin among all subjects (p=0.0012, R²=0.34) and in TI-α (p=0.0213, R²=0.61), but the relationship was not significant in β-thalassemia (p=0.5198). ECV increased with age in all subjects (p=0.0148, R²=0.21), particularly in β-thalassemia (p=0.0060, R²=0.35), but not in TI-α (p=0.6086). Both hemoglobin and age were retained in a multivariate model (p=0.0017, p=0.0196, respectively; R²=0.47), while their interaction was not significant.

Discussion

The most concerning finding is the presence of significant ECV elevation in 3/4 young, asymptomatic NTDT-TI-α patients. We found that ECV is strongly associated with anemia severity in thalassemia, particularly in TI-α. These findings are consistent with the emerging data in TDT, NTDT and other ineffective erythropoiesis-related chronic anemias showing long-term morbidity and mortality is worse with lower hemoglobin. This is clinically important given that implementation of regular transfusion in NTDT was associated with improved morbidity and survival. The multivariate model of ECV in this study shows the long-term effects of anemia and age on fibrosis, and we hypothesize that duration of anemia is important. Larger studies are needed to evaluate the prevalence of myocardial fibrosis and the consequence of diastolic dysfunction and arrhythmia at older ages in this population. Little is known about the outcomes of NTDT-TI-α in older individuals, but this preliminary data suggests this presumed benign disorder is likely similar to NTDT in general.