Download CARDIAC DYSFUNCTION - Thalassemia Center

Reversal of Cardiac Failure in
Thalassemia
Dr Khawla Belhoul
Director Thalassemia Center
Interdepartmental meeting
November 2008
Cardiomyopathy
kills
young patients with
Thalassemia
Heart failure
is the leading cause of death
in patients with ß-thalassemia major
60%mortality
Iron cardiomyopathy
is preventable
is treatable
is reversible
Multifactorial aetiology of heart failure
in Thalassemia patients
– Iron overload
– Chronic haemolysis
– High cardiac output state
– Tissue hypoxia.
– Endocrine deficiencies.
– Metabolic deficiencies
– Myocarditis.
– Immunogenic.
– Genetic : the ApoE 4 allele
Iron Cardiomyopathy
Causes of Iron Overload
– Transfusion related.
– Iron hyperabsorption and maldistribution.
– tissue hypoxia ->reduction of hepcidin levels > leads to iron hyperabsorption and
maldistribution.
– urinary hepcidin was found to be suppressed
in TM and TI patients.
– down-regulation of hepcidin is proportional to
the increase of erythropoietic activity.
Iron Cardiomyopathy
• Is a restrictive cardiomyopathy that manifests
itself as systolic or diastolic dysfunction.
• Iron induced oxidative.
• Iron induced cardiac fibrosis (Angiotensin II).
Chronic Hemolysis Oxidative Stress
free heme and the RBC membrane elements
A nitric oxide and arginine
vasoconstriction.
endothelial dysfunction,
Other endocrine comorbidities
•
Hypoparathyroidism can produce
hypocalcaemia cardiomyopathy
•
Severe growth hormone deficiency is
associated with cardiomyopathy
•
Adequate thyroid hormone levels are vital for
cardiac function
•
Good glycemic control lowers oxidative stress
Nutritional comorbidities
• Carnitine
– Single –arm studies suggest improved cardiac
systolic/diastolic function
• B complex vitamines
– Severe deficiency in B1 ,B6 are common
– Role in heart failure is unknown.
• Vitamin D deficiency
– Correlated with cardiac dysfunction /CHF in non
thalassaemic cardiac and renal failure patients
– Correlated with LVEF in TM
• Selenium, zinc??
Multifactorial aetiology of heart failure
in Thalassemia patients
– Iron overload
– Chronic haemolysis
– High cardiac output state
– Tissue hypoxia.
– Endocrine deficiencies.
– Metabolic deficiencies
– Myocarditis.
– Immunogenic.
– Genetic : the ApoE 4 allele
We are no more powerless
to predict
WHO is at risk ??
MRI T2*
MRI T2*
• MRI remains the only non-invasive modality in clinical use with the
ability to detect cardiac iron deposition.
• Reductions in cardiac iron assessed by MRI correlate with
improvements in cardiac function .
• In general, the lower the T2* the higher the risk of cardiac
dysfunction.
• T2* <8 ms suggestive of severe iron overload
• MRI T2* is has improved our ability to detect those patients at risk.
• MRI T2* has allowed us to compare the cardiac benefits of different
Chelation regimens.
T2* - CARDIAC RISK RANGING
Below a myocardial T2* of 20 ms, there was a progressive and significant decline in LVEF ( P<0·0001)
High
Intermediate
Low
HEART T2* IN INCIDENT HEART FAILURE
8
Mean=6.7 +/- 2.4ms
7
n=28
Frequency
6
89% <10ms
5
4
3
2
1
0
2-3
3-4
4-5
5-6
6-7
7-8
8-9
9-10
10-11
11-12
12-13
Heart T2* (ms)
All patients T2* >20ms no heart failure, unless congenital heart disease
All patients T2* >20ms no heart failure, unless congenital heart disease
Reference: Tanner M. ASH Abstracts 2005
Iron cardiomyopathy
is preventable
is treatable
is reversible
What is the ideal iron
chelator ?
The ideal iron chelator
DEFERIPRONE INDUCED AGRANULOCYTOSIS
• Agranulocytosis remains the major concern for patients
receiving deferiprone.
• occurs in less than 1% of patients who undergo weekly
monitoring of their blood counts .
• Milder neutropenia (500–1500/mm3) occurs in about 8% of
patients.
DEFERIPRONE INDUCED AGRANULOCYTOSIS
Three important questions about deferiprone and
agranulocytosis remain incompletely answered.
– First, does the currently recommended weekly
monitoring of blood counts during deferiprone
therapy reduce the risk of agranulocytosis ?
– Second, should weekly monitoring continue
indefinitely?
– Third, should patients who develop
agranulocytosis be re-treated with deferiprone
after their neutrophil counts return to normal?
DEFEROXAMINE IN HEART FAILURE
• 7 patients presenting with heart failure
• All patients given IV deferoxamine for 12
months
• CMR of T2* and LV function at 0, 3, 6, and 12
months
Reference: Anderson LJ. Br J Haematol 2004;127:348
MYOCARDIAL T2*
REPRODUCIBILITY IN TRIAL
• 1 patient died
– Liver iron 4.1 mg/g dry weight
– Myocardial iron 5.9 ms (normal >20 ms)
• 6 survivors
Reference: Anderson LJ. Br J Haematol 2004;127:348
REVERSAL OF MYOCARDIAL SIDEROSIS
T2* ms
T2* ms
n=6, p=0.003
n=6, p=0.003
Reference: Anderson LJ. Br J Haematol 2004;127:348
CONCOMITANT IMPROVED LV FUNCTION
n=6
p=0.03
p=0.02
p=0.02
p=0.03
Reference: Anderson LJ. Br J Haematol 2004;127:348
LA16: MYOCARDIAL T2*
Deferiprone
Deferoxamine
p=0.77
p=0.040
Reference: Pennell DJ et al. Blood 2005 e-pub December 22nd
p=0.023
DEFEROXAMINE ALONE VS COMBINATION Rx
T2*
P<0.001
Combined
P=0.074
Heart
Deferoxamine
Liver
Reference: Tanner MA. ASH 2005 abstracts
Between groups
p=0.017
Management acute congestive Cardiac failure in
Thalassemia patients
• Try to exclude viral myocarditis and thyroid
disorders. Look for history of chest pain and/or flue
like.
• Perform FBC,U&E,CA, CR, CRP,ESR , autoimmune
screen, cardiac enzymes ,T3,T4 ,TSH, ECG,
Thrombophilia screen, Echo &
• T2* MRI once stable ;if not done recently
Management acute congestive Cardiac failure in
Thalassemia patients
• Conventional heart failure treatment
• Give hydrocortisone : under stress these patients are likely to
require steroid supplements due to occult adrenal insufficiency.
• Once hemodynamically stable start continuous infusion of
DFO (Deferoxamine) 40 mg/kg/day.
• On day 6 of chelation and if the patient condition is stable
add Deferiprone 75 mg/kg/day p.o.
• Continue the iv chelation for at least 10days.
• Day 11 of chelation shift to subcutaneous DFO 50
mg/kg/day . Continue oral Deferiprone.
• day 21 increase Deferiprone dose to 100mg/kg/day and
continue Desferal as before .
• Keep hemoglobin levels > 9 g/dL.
Precautions with parenteral administration of Desferal:
• Desferal should be prepared as a 10% solution in water for
injections.( 5 mL water+ 500 mg Desferal powder).
• The 10% Desferal solution to be further diluted with (sodium
chloride, glucose, Ringer's solution).
• Rates of infusion should not exceed 15 mg/kg/hr.
• Always start Intravenous Desferal slowly as fast initial
infusions may lead to severe hypotension and shock (e.g.
flushing, tachycardia, urticaria and collapse).
Transfusion protocol adjustment for Thalassemia
Patients Who Have Cardiac Problem:
• Pre transfusion Hb >9.5 g/dl
• PRBC transfusion rate 2ml/kg/hr
• Give prophylactic Frusemide 20 mg IV if pre
Hb level <7 g/dl
Risk factors modifications
• Hypertension
• Serum lipid
• Optimizing body weight
• Smoking cessation
• Alcohol abstinence
• Control of blood sugar
TREATMENT OF
ESTABLISHED CARDIOMYPATHY
• Arrhythmias respond more quickly to
chelation than cardiac function .
• Amiodarone is the drug of choice
• Catheter ablation is contraindicated.
• ICD’s should be avoided unless there
is documented arrhythmia-associated
syncope or aborted sudden death.
• Treat aggressively and don’t give up
early.
• Consider even cardiac transplantion
if necessary.
TREATMENT OF
ESTABLISHED CARDIOMYPATHY
• Aggressive Chelation; aggressive Chelation
• Correction of endocrine deficiencies
• Correction of metabolic deficiencies
• Arrthymia control
• Convential heart failure medications
• No blame environment
• Start by blaming yourself
• Accept open criticism and difficult arguments
and discussions it creates strong environment
and people
• Family environment and team work comes
only if you keep sensitivity at home.
• Change can start down and propagate to
higher authority
.