European Heart Journal (2001) 22, 2140-2141
`doi:10.1053/euhj.2001.2951, available online at hitp:/Avww.idealibrary.com on DEL
`
`Diagnosing myocardial iron overload
`
`See page 2171, doi:10.1053/euhj.2001.2822 for
`article to which this Editorial refers
`
`the
`
`Cardiac failure or arrhythmia are the dominant
`causes of death in patients with thalassaemia major
`and other
`transfusion-dependent
`refractory anae-
`mias. Each unit of blood contains 200-250 mg of iron
`and body iron stores are normally only 0-5—1-5 g.
`Since the body has no physiological mechanism for
`excreting iron, repeated blood transfusions result in
`iron accumulation in the reticuloendothelial system
`and parenchymal cells. The principal damage occurs
`to the heart, liver and endocrine organs. The rate of
`iron accumulation is on average 0-5 mg. kg~! body
`weight per day and iron chelation therapy must
`be given to cause excretion of this amount of iron
`and so prevent early mortality from an iron-induced
`cardiomyopathy.
`The most widely used iron chelating drug, and the
`only onelicensed worldwide,is desferrioxamine. With
`the introduction of self-administered slow subcutane-
`ous daily infusions of this drug in 1976~7"! the
`life expectancy of patients with thalassaemia major
`improved dramatically?-“1, Desferrioxamine is, how-
`ever, expensive and has toxic or allergic side effects
`in a numberof patients. Compliance with the arduous
`daily infusion regime is often poor,
`especially
`in teenagers and this results in reduced patient
`survival>-4,
`The mechanisms by which iron damages myocar-
`dial cells has been extensively studied in vitro by
`Link, Hershko and co-workers!?!, Clinically it has
`proved difficult to predict at an carly stage which
`patients are particularly at risk of dying from an
`iron-induced cardiomyopathy. Various indirect tests
`that have been investigated include measurement of
`serumferritin, of liver iron, of non-transferrin bound
`iron in plasma!*!, as well as direct tests of cardiac
`function including electro- and echocardiography and
`multigated angiography (MUGA) scanning, Some
`studies have suggested that maintenance of serum
`ferritin below 2500 ug.1~! is essential”! but many
`patients with ferritin levels below this level have died
`from a cardiomyopathy. Based on data on genetic
`haemochromatosis,
`liver iron measured chemically
`after biopsy has been proposedas the ‘gold standard’.
`A level over 15mg. g~! dry weight (80 pmol. g7!
`liver wet weight) predicted short survival!!!_ This
`particular dividing line has not been validated for
`
`Published online 4 October 2001.
`
`patients with thalassaemia major, althoughclearly, the
`greater the body iron burden, the greater the risk of
`cardiac and other complications of iron overload!!”!,
`In the present study, Anderson and colleagues!!!)
`have developed a new reproducible non-invasive
`method for measuring cardiac (or liver) iron. As the
`authors explain, previous attempts to measure car-
`diac iron using spin-ECHO techniques have failed
`because of lack of sensitivity, motion artefacts and
`poorsignal-to-background noise ratios. Electrocardi-
`ography and stress echoradiography have not de-
`tected early damage. They use a cardiac T2-star (T2*)
`technique, a relaxation parameter which depends
`mainly on heterogeneity in the local magnetic field.
`The result is increased iron overload. They found a
`good inverse correlation between the patients’ myo-
`cardial T2* andleft ventricular ejection fraction but
`no significant correlation between myocardial T2*
`and serum ferritin or liver iron. There was also a
`significant correlation between myocardial T2* and
`the need for cardiac medication.
`The principal value of this new non-invasive tech-
`nique is in the early detection of cardiomyopathy
`whileit is still reversible. Although in some cases even
`severe cardiomyopathy induced by iron can be re-
`versed!'?], this is often not possible. Myocardial T2*
`provides the earliest, and probably the mostsensitive
`and reproducible test yet available of cardiac iron and
`consequent cardiac damage. Protocols are being ex-
`plored for the removal of this cardiac iron by the use
`of more intensive desferrioxamine treatment!! or
`with deferiprone, an orally active iron chelating
`drug"or with a combination of the two drugs"! *!,
`Deferiprone is now licensed in the European Union,
`India and other countries.
`It has a much lower
`molecular weight (139) than desferrioxamine. Thereis
`evidence that it is able to penetrate cells, including
`myocardial cells, and remove iron directly!A
`combination of the drug with desferrioxamine has
`been postulated to have a ‘shuttle’ effect,
`in which
`deferiprone removes iron from cells and then passesit
`to desferrioxamine which results in its rapid excretion
`in urine and faeces!!®!. The combined therapy is
`additive in increasingurine iron excretion!) and may
`result
`in increased compliance by reducing the
`number of days each week desferrioxamine must be
`infused and the number of capsules of deferiprone
`(which can cause nausea) to be swallowed each day.It
`may also help to avoid toxic effects of both drugs
`since lower doses may be satisfactory when the drugs
`are used in combination, rather than alone.
`
`© 2001 The European Society of Cardiology
`
`Apotex Tech.
`Ex. 2036
`
`Apotex Tech.
`Ex. 2036
`
`

`

`Editorials 214]
`
`
`It will be importantto use the T2° technique to see
`how well the drugs alone or in combination prevent
`myocardial iron accumulation or remove myocardial
`iron and reverse cardiac damage in the face of con-
`tinuing blood transfusions. It is hoped that other
`groups will adopt this new technique and provide
`confirmatory data on its value for assessing myocar-
`dial iron. Since it is a sophisticated and expensive
`technique, however,it is not practicable for introduc-
`tion into many poor countries where thalassaemia
`major is most common. It is hoped, however, that
`with the T2* technique it may be possible to reassess
`the value of simpler tests of iron overload and cardiac
`dysfunction which maybefeasible to perform in poor
`countries.
`
`A. V. HOFFBRAND
`Royal Free Hospital,
`London, U_K.
`
`References
`
`{1] Hussain MAM, Fiynon DM, Green N, Hussein S, Hoffbrand
`AV. Subcutaneous infusion and intramuscular injection of
`desferrioxamine in patients with transfusional iron overload.
`Lancet 1976; 2: 1278-80.
`{2] Propper RL, Cooper B, Rufo RR et ai. Continuous subcu-
`taneous administration of deferoxamine in patients with iron
`overload. N Engi J Med 1977; 297: 418-23.
`[3] Zurlo MF, DeStefano P, Borgna Pignatti C et al. Survival and
`causes of death in thalassaemia major. Lancet 1989; 2: 27-30.
`{4} Gabutti V, Piga A. Results of long-term iron chelating
`therapy. Acta Haematologica. 1996; 95: 26-36.
`
`
`
`[5] Wolfe L, Olivieri N, Sallam D e7 al. Prevention of disease
`by subcutaneous deferoxamine in patients with thalassemia
`major. N Engl J Med 1985; 312: 166-1603.
`{6] Aldouri MA, Hoffbrand AV, Flynn DM eftal. High incidence
`of cardiomyopathy in beta thalassaemia patients receiving
`transfusion and iron chelation: reversal by intensified chela-
`tion. Acta Haemato 1990; 84: 113-7.
`{7] Link G, Saada A, Pinson A, Konijn AM, Hershko C.
`Mitochondrial respiratory enzymes are a major target of iron
`toxicity in rat heart cells. J Lab Clin Med 1998; 131: 466-74.
`[8] Al-Refaie FN, Wickens DG, Wonke B, Kontoghiorghes GJ,
`Hoffbrand AV. Serum iron-transferrin-bound iron in beta-
`thalassaemia major patients treated with desferrioxamine and
`Li. Br J Haemat 1992; 82: 431-6.
`[9] Olivieri NF, Nathan DG, MacMillan JH et al. Survival in
`medically treated patients with homozygous # thalassemia.
`N Engl J Med 1994; 331: 574-8.
`[10] Olivieri NF, Brittenham GM.Iron-chelating therapy and the
`treatment of thalassemia. Blood 1997; 89: 739-61.
`[11] Anderson L, Helden S, Davis B et al. Cardiovascular T2-star
`(T2*) magnetic resonance for the early diagnosis of myocar-
`dial iron overload. Eur Heart J 2001; 22: 2171-9, doi:10,1053/
`euhj.2001.2822.
`{12] Marcus RE, Davies SC, Bartock HM, Underwood SR,
`Walton S, Huehns ER. Desferrioxamine to improve cardiac
`function in iron-overloaded patients with thalassaemia major.
`Lancet 1984; 1: 392.
`[13] Porter JB. A risk benefit assessment of iron-chelation therapy.
`Drugs Safety 1997; 17: 407-21.
`[14] Barman Balfour KA, Foster RH. Deferiprone: A review ofits
`clinical potential in iron overload in #-thalassaemia major and
`other transfusion-dependent diseases. Drugs 1999: 3: 553-78.
`(15] Wonke B, Wright C, Hoffbrand AV. Combined therapy with
`deferiprone and desferrioxamine. Br J Hacmat 1998; 103:
`361-4,
`[16] Breuer W, Erners MJJ, Pootrakul P, Abramov A, Hershko C,
`Cabantenik ZI. Desferrioxamine-chelatable iron a component
`of serum non-transferrin-bound iron, used for assessing
`chelation therapy. Blood 2001; 97: 792-8.
`
`European Heart Journal (2001) 22, 2141-2143
`doi:10.1053/euhj.2001.2831, available online at http://www.idealibrary.com on IDEL”
`
`Dofetilide: what role in the treatment of ventricular
`tachyarrhythmias?
`
`See page 2180, doi: 10.1053/euhj.2001.2679 for the
`article to which this Editorial refers
`
`In the presentissue Boriani ef al!report the results
`of a prospective double-blind randomized crossover
`study,
`in which the short- and long-term efficacy
`and safety of oral dofetilide or oral sotalol were
`compared in 135 patients with ischaemic heart disease
`and inducible sustained ventricular
`tachycardia.
`
`Published online 2 October 2001.
`
`Dofetilide was as efficacious as sotalol in preventing
`the induction of sustained ventricular tachycardia,
`which wasachieved in onethird of the patients. There
`was no concordance in the response to the two drugs.
`During the acute phase dofetilide was significantly
`better tolerated than sotalol. However, during long-
`term treatment, which was not randomized, both
`drugs were well tolerated.
`This study is based on the use of electrophysiologi-
`cal
`testing as a guide for selecting antiarrhythmic
`drug therapy in ventricular
`tachyarrhythmias, a
`
`‘© 2001 The European Society of Cardiology
`
`Apotex Tech.
`Ex. 2036
`
`Apotex Tech.
`Ex. 2036
`
`