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Cardiac Effects of Iron Overload
Dudley Pennell, MD, FRCP, FACC, FESDirector, CMR Unit
Royal Brompton HospitalProfessor of Cardiology
National Heart and Lung InstituteImperial College
London, United Kingdom
Death by heart failure in 71% of patients Median age at death: 35 years
Why Is the Heart Important in Thalassemia Major?
IO = iron overload Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42-50.
Cardiac Iron Toxicity
Fibroblast
Stimulate fibrotic response
Iron uptakeIron storageIron interactionsGene expression
Fe2+
Fe3+Depolarization and repolarization
Intracellular ion concentrations
Sarcoplasmicreticulum
Ryanodine-sensitivecalcium reuptake
Excitation/contractioncoupling
Mitochondria
Respiratory chainenzymes
Lysosomes
Liposomal membrane
damage
More free iron
Nucleus
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.
DMT1 = divalent metal transporter 1; LVDC = L-type voltage-dependent channels; NTBI = non-transferrin-bound iron; Tf = transferrin
LVDC
Tf-Fe
Tf-mediated(minimal)
Fe2+
Fe3+DMT1
???
NTBIK+
Na+
Na+ - Ca2+
Na+ - K+ ATPase
5 ms 6 ms 7 ms 8 ms 9 ms 11 ms 13 ms 15 ms 17 ms
Measuring Myocardial T2*
Signal = Ke-TE/T2*
TE = echo timeAnderson LJ. Eur Heart J. 2001;22:2171-2179.
Normal ModerateSevere
Normal ModerateSevere
Kaplan-Meier Curves: T2* and Heart Failure
Kirk P. Circulation. 2009;120:1961-1968.
< 6 ms
6-8 ms
8-10 ms
> 10 ms
Follow-up Time (days)Prop
ortio
n of
Pati
ents
With
Hea
rt F
ailu
re
T2* - Cardiac Risk Ranging
Anderson LJ. Eur Heart J. 2001;22:2171-2179.
Left
Ven
tric
ular
Eje
ction
Fra
ction
(%)
Heart T2* (ms)
90
80
70
60
50
40
30
20
10
0 10 20 30 40 50 60 70 80 90 100
High Intermediate Low
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 deferiprone vs 13% with DFO; P = .023
– Increase in LVEF 3.1% with deferiprone vs 0.3% with DFO; P = .003
DFO = deferoxamine; LVEF = left ventricular ejection fractionPennell D, et al. Blood. 2006;107:3738-3744.
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 vs continued 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.
EPIC Cardiac Substudy: Cardiac T2* in Treatment Arm
7.4 8.2‡
14.6
17.4**
11.212.9†
02468
101214161820
Baseline 12
Time (months)
Mea
n Ca
rdia
c T2
* (m
s)
**n = 64, P < .0001; †n = 105, P < .0001; ‡n = 41, P = .0002.Pennell D, et al. Blood. 2010;115:2364.
65.2
68.2
66.165.8
68.768.4
67.167.7
67.4
55
60
65
70
75
Baseline 6 12
Time (months)M
ean
LVEF
(%)
80
P = .53
No change
10 to < 20 ms> 5 to < 10 ms
all patients
EHA 2010: EPIC Cardiac Substudy ExtensionMyocardial T2* Over 2 Years in Patients With Beta Thalassemia and Myocardial Siderosis
Pennell D, et al. Presented at EHA 2010. Abstract 498.
Mean deferasirox dose: •33.1 mg/kg/d in core study•36.1 mg/kg/d during extension
Time (months)Geo
met
ric M
ean
Myo
card
ial T
2* (m
s)
*
*
*
*
*
*
* P < .001 versus baseline
N = 101 N = 101 N = 85
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.
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 ferritinPennell D, et al. Published at EHA 2010. Abstract 1805.
Prior DFO Monotherapy (n = 63)
Prior DFO-DPO (n = 32)
↑ in geometric mean for myocardial T2* 28%1 35%1
% of pts with increase > 4% in T2* 79% 69%
Mean change in LVEF 1.2% ± 4.5%2 −1.7 % ± 5.8% [NS]
↓ in mean LIC 9.6 ± 12.7 mg Fe/g dw3 12.4 ± 12.5 mg Fe/g dw3
↓ in median SF 2227 ng/mL3 2559 ng/mL3
1. P < .0001. 2. P = .046. 3. P < .001.
CORDELIA: RCT Deferasirox vs DFO
Continuing in the extension is optional and requires re-consent by participants.
Screening 23 days
1-year study Rx in Core study
96 patients deferasirox
96 patients DFO
1-year study Rx in Extension study
96 patients deferasirox
96 patients DFO
Randomize eligible patients(1:1 ratio)
Followed by 5-day washout
Screening 23 days
End Core / Start Extension
End Extension
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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