Accelerated atherosclerosis in beta-thalassemia

Area of Science:

• Cardiovascular Biology
• Hematology
• Metabolic Diseases

Background:

• Beta-thalassemia (BT) is associated with increased carotid intima-medial thickness, a marker of premature atherosclerosis.
• The direct link between BT pathophysiology and atherosclerotic disease progression remains unclear.
• Heme-mediated oxidative stress is hypothesized to promote atherosclerosis in BT due to hemolytic anemia and increased free heme.

Purpose of the Study:

• To investigate the direct relationship between beta-thalassemia and atherosclerotic disease.
• To evaluate the therapeutic potential of hemopexin (HPX) and deferiprone (DFP) in mitigating BT-associated atherosclerosis.

Main Methods:

• Utilized wild-type (WT) and BT mice fed a high-fat diet with PCSK9 gain-of-function mutation.
• Administered adeno-associated virus (AAV)-mediated hemopexin (HPX) therapy.
• Assessed the impact of deferiprone (DFP)-mediated iron chelation.
• Quantified atherosclerotic plaque burden via aortic en face and aortic root lesion analysis.

Main Results:

• BT mice exhibited significantly elevated atherosclerotic plaque accumulation compared to WT controls.
• HPX therapy reduced plaque area in both BT mice and a phenylhydrazine-induced hemolysis model.
• DFP treatment decreased atherosclerosis in BT mice but offered no additive benefit when combined with HPX.

Conclusions:

• Beta-thalassemia directly accelerates atherosclerosis, driven by intravascular hemolysis and increased free heme.
• Hemopexin therapy effectively reduces atherosclerotic plaque burden in models of BT and hemolysis.
• Iron chelation shows efficacy but does not enhance the benefits of hemopexin therapy in this context.