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Cardiac Effects of Iron Overload

Cardiac Effects of Iron Overload. Dudley Pennell, MD, FRCP, FACC, FES Director, CMR Unit Royal Brompton Hospital Professor of Cardiology National Heart and Lung Institute Imperial College London, United Kingdom. Why Is the Heart Important in Thalassemia Major?.

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Cardiac Effects of Iron Overload

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  1. Cardiac Effects of Iron Overload Dudley Pennell, MD, FRCP, FACC, FES Director, CMR UnitRoyal Brompton Hospital Professor of Cardiology National Heart and Lung Institute Imperial College London, United Kingdom

  2. Why Is the Heart Important in Thalassemia Major? Death by heart failure in 71% of patients Median age at death: 35 years % of UK Thalassemia Major Deaths IO = iron overload Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42-50.

  3. Cardiac Iron Toxicity Fibroblast Stimulate fibrotic response LVDC Ryanodine-sensitive Sarcoplasmic Lysosomes calcium reuptake reticulum Fe2+ More free iron NTBI Excitation/contraction DMT1 Fe3+ Liposomal coupling membrane 2+ ??? Fe damage Mitochondria K+ Depolarization and Respiratory chain 3+ repolarization enzymes Fe Tf-mediated Na+ (minimal) Tf-Fe Nucleus Na+ - Ca2+ Intracellular ion DMT1 = divalent metal transporter 1; LVDC = L-type voltage-dependent channels; NTBI = non-transferrin-bound iron; Tf = transferrin concentrations Na+ - K+ ATPase Gene expression Iron storage Iron uptake Iron interactions When the antioxidant capacity of the cell is exceeded, ROS are formed, damaging organelles, interfering with electrical and mechanical processes, and triggering apoptosis. ROS = reactive oxygen species. Wood JC, et al. Ann NY Acad Sci. 2005;1054:386-395.

  4. 5 ms 6 ms 7 ms 8 ms 9 ms 11 ms 13 ms 15 ms 17 ms Normal Moderate Severe Measuring Myocardial T2* Signal = Ke-TE/T2* TE = echo time Anderson LJ. Eur Heart J. 2001;22:2171-2179.

  5. Kaplan-Meier Curves: T2* and Heart Failure < 6 ms 6-8 ms Proportion of Patients With Heart Failure 8-10 ms > 10 ms Follow-up Time (days) Kirk P. Circulation. 2009;120:1961-1968.

  6. T2* - Cardiac Risk Ranging 90 80 70 60 Left Ventricular Ejection Fraction (%) 50 40 30 20 10 40 50 90 100 0 Heart T2* (ms) 20 30 60 70 80 10 High Intermediate Low Anderson LJ. Eur Heart J. 2001;22:2171-2179.

  7. Deferiprone vs DFO in Beta Thalassemia Major With Asymptomatic Myocardial Siderosis • RCT in 61 pts previously maintained on sc DFO • Compared continued DFO maintenance 43 mg/kg/d vs switch to oral deferiprone 90 mg/kg/d • At 12 months: • Improvement in myocardial T2* 27% with deferipronevs 13% with DFO; P = .023 • Increase in LVEF 3.1% with deferipronevs 0.3% with DFO; P = .003 DFO = deferoxamine; LVEF = left ventricular ejection fraction Pennell D, et al. Blood. 2006;107:3738-3744.

  8. Effect of Combined DFO + Deferiprone vs Placebo on Cardiac Iron in Thalassemia Major • Randomized, placebo-controlled trial in 65 pts previously maintained on subcutaneous DFO • Compared continued DFO maintenance + placebo vscontinued DFO maintenance + deferiprone • At 12 months: • Increase in geometric mean for myocardial T2* 50% with combination vs 24% with placebo; P = .02 • Increase in absolute LVEF 2.6% with combination vs 0.6% with placebo; P = .05 Tanner MA. Circulation. 2007;115:1876-1884.

  9. EPIC Cardiac Substudy: Cardiac T2* in Treatment Arm 20 80 > 5 to < 10 ms all patients 10 to < 20 ms 18 17.4** No change 16 75 14.6 14 12.9† 12 70 68.7 68.4 68.2 11.2 Mean Cardiac T2* (ms) 67.4 Mean LVEF (%) 10 67.1 67.7 65.2 65.8 65 8.2‡ 8 66.1 7.4 6 60 4 P = .53 2 55 0 Baseline 6 12 Baseline 12 Time (months) Time (months) **n = 64, P < .0001; †n = 105, P < .0001; ‡n = 41, P = .0002.Pennell D, et al. Blood. 2010;115:2364.

  10. EHA 2010: EPIC Cardiac Substudy Extension Myocardial T2* Over 2 Years in Patients With Beta Thalassemia and Myocardial Siderosis • Mean deferasirox dose: • 33.1 mg/kg/d in core study • 36.1 mg/kg/d during extension * * * * Geometric Mean Myocardial T2* (ms) * * * P < .001 versus baseline N = 101 N = 101 N = 85 Time (months) Pennell D, et al. Presented at EHA 2010. Abstract 498.

  11. EHA 2010: EPIC Cardiac Substudy Extension(cont) After 2 years of deferasirox treatment: • 57% of patients with mild-to-moderate baseline cardiac siderosis (10 to < 20 ms) were normalized ( ≥ 20 ms) • 43% of patients with severe baseline cardiac siderosis (> 5 to < 10 ms) improved to mild-to-moderate category Pennell D, et al. Presented at EHA 2010. Abstract 498.

  12. EHA 2010: EPIC Cardiac Substudy Extension: Stratified by Previous Chelation Regimen • Evaluated effect of 2 years of deferasirox treatment in patients with beta thalassemia and myocardial siderosis • Stratified by prior chelation (DFO or combined DFO-DPO) DPO = deferiprone; dw = dry weight; LIC = liver iron concentration; SF = serum ferritin Pennell D, et al. Published at EHA 2010. Abstract 1805.

  13. CORDELIA: RCT Deferasirox vs DFO 1-year study Rx in Core study 1-year study Rx in Extension study Screening 23 days Screening 23 days 96 patients deferasirox 96 patients deferasirox 96 patients DFO 96 patients DFO Randomize eligible patients(1:1 ratio) Followed by 5-day washout End Extension End Core / Start Extension Continuing in the extension is optional and requires re-consent by participants.

  14. Conclusions • Cardiac disease is the leading cause of death in beta thalassemia major • T2* MRI scan is useful for early detection of cardiac IO and cardiac risk ranging • Deferasirox, deferiprone, and deferiprone+DFO are shown to significantly improve myocardial T2* • Deferiprone is shown to improve LVEF • EHA 2010: First prospective 2-year data on cardiac iron removal with chelation • Continued therapy with deferasirox ≥ 30 mg/kg/d effectively removed cardiac iron, well tolerated

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