title: Left ventricular torsional mechanics and myocardial iron load in beta-thalassaemia major: a potential role of titin degradation.
abstract: BACKGROUND
  Iron may damage sarcomeric proteins through oxidative stress. We explored the left ventricular (LV) torsional mechanics in patients with beta-thalassaemia major and its relationship to myocardial iron load. Using HL-1 cell and B6D2F1 mouse models, we further determined the impact of iron load on proteolysis of the giant sarcomeric protein titin.
  
  
  RESULTS
  In 44 thalassaemia patients aged 25 ± 7 years and 38 healthy subjects, LV torsion and twisting velocities were determined at rest using speckle tracking echocardiography. Changes in LV torsional parameters during submaximal exercise testing were further assessed in 32 patients and 17 controls. Compared with controls, patients had significantly reduced LV apical rotation, torsion, systolic twisting velocity, and diastolic untwisting velocity. T2* cardiac magnetic resonance findings correlated with resting diastolic untwisting velocity. The increments from baseline and resultant LV torsion and systolic and diastolic untwisting velocities during exercise were significantly lower in patients than controls. Significant correlations existed between LV systolic torsion and diastolic untwisting velocities in patients and controls, both at rest and during exercise. In HL-1 cells and ventricular myocardium of B6D2F1 mice overloaded with iron, the titin-stained pattern of sarcomeric structure became disrupted. Gel electrophoresis of iron-overloaded mouse myocardial tissue further showed significant decrease in the amount of titin isoforms and increase in titin degradation products.
  
  
  CONCLUSIONS
  Resting and dynamic LV torsional mechanics is impaired in patients with beta-thalassaemia major. Cell and animal models suggest a potential role of titin degradation in iron overload-induced alteration of LV torsional mechanics.
authors.forename: Mei-Pian
authors.initials: MP
authors.lastname: Chen
authors.forename: Shu-Na
authors.initials: SN
authors.lastname: Li
authors.forename: Wendy W M
authors.initials: WW
authors.lastname: Lam
authors.forename: Yuen-Chi
authors.initials: YC
authors.lastname: Ho
authors.forename: Shau-Yin
authors.initials: SY
authors.lastname: Ha
authors.forename: Godfrey C F
authors.initials: GC
authors.lastname: Chan
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China. xfcheung@hku.hk.
authors.forename: Yiu-Fai
authors.initials: YF
authors.lastname: Cheung
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001696:Biomechanical Phenomena; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D011446:Prospective Studies; D011494:Protein Kinases / Q000378:metabolism*; D059748:Proteolysis; D013789:Thalassemia / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D054159:Torsion, Mechanical; D014463:Ultrasonography; D016277:Ventricular Function, Left; D055815:Young Adult
chemical_list: D007501:Iron; D011494:Protein Kinases; C579730:titin protein, mouse
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