Cardiac complications in beta-thalassemia: From mice to men

Abstract

Iron overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. Since investigation of iron overload cardiomyopathy in thalassemia patients has many limitations, a search for an animal model for this condition has been ongoing for decades. In the past decades, there is no doubt that the use of b-thalassemic mice as a study model to investigate the pathophysiology of iron overload cardiomyopathy and the role of various pharmacological interventions, has shed some light in understanding this serious complication and in improving the associated cardiac dysfunction. In this review, the effects of iron overload on the hearts of b-thalassemic mice under conditions of iron overload as well as the efficacy of pharmacological interventions to combat these adverse effects on the heart are reviewed and discussed. AbstractBeta-thalassemia is an inherited hemoglobin disorder caused by reduced or absent synthesis of the beta globin chains of hemoglobin. This results in variable outcomes ranging from clinically asymptomatic to severe anemia, which then typically requires regular blood transfusion. These regular blood transfusions can result in an iron overload condition. The iron overload condition can lead to iron accumulation in various organs, especially in the heart, leading to iron overload cardiomyopathy, which is the major cause of mortality in patients with thalassemia. In the past decades, there is no doubt that the use of b-thalassemic mice as a study model to investigate the pathophysiology of iron overload cardiomyopathy and the role of various pharmacological interventions, has shed some light in understanding this serious complication and in improving the associated cardiac dysfunction. In this review, the effects that iron overload has on the hearts of b-thalassemic mice under conditions of iron overload as well as the efficacy of pharmacological interventions to combat these adverse effects on the heart are reviewed and discussed. The in-depth understanding of biomolecular alterations in the heart of these iron overload thalassemic mice will help give guidance for more effective therapeutic approaches in the near future.

CaM kinase II regulates cardiac hemoglobin expression through histone phosphorylation upon sympathetic activation

“…Notably, cardiomyopathy is a well-known lifespan limiting complication of β-thalassemia major (caused by genetic deletion of β-globins) and is traditionally thought to be mainly mediated by iron overload (46). However, despite a decrease in mortality due to the treatment with iron chelators, the phenotype persists (both in the human disease and in mouse models) (47). From this point of view, it would be important to clinically monitor cardiac function in the context of new "curative" approaches in "exthalassemic" patients by hematopoietic stem cell transplantation or gene therapy (48).…”

Involvement of cytosolic and mitochondrial iron in iron overload cardiomyopathy: an update

“…As for iron overload models using genetically modified animals, hemojuvelin knockout mice when fed a high iron diet [21, 22, 85] and beta-thalassemic mice given either iron dextran injections [47] or feed an iron enriched diet [64] have been used to mimic cardiac iron overload in patients with juvenile hemochromatosis and transfusion dependent beta-thalassemia, respectively. These genetically altered mouse models are thought to be more suitable for investigating the pathophysiology and treatment of IOC in hereditary hemochromatosis and β-thalassemia conditions.…”

Clinical Complications of Beta-Thalassemia Major

“…Cardiomyopathy and arrhythmia in β-TM are the most important complications caused by iron overload accounting for 71% of deaths globally (49) . Patients with β-TM undergo chronic hemolysis that causes anemia; if left untreated leads to increased cardiac output, which ultimately results in left ventricular (LV) dilatation and hypertrophy ending with high rate heart failure (HF).…”

“…In β-TM normal myocardial T2* (T2*˃ 20 ms) is associated with normal LV and RV ejection fraction (EF). On the other hand, lower myocardial T2* (T2*˂20) is associated with LV and RV dysfunction, and an improvement in T2* results indicate improvement in LV and RF ejection fraction (49,52,53) .…”