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