revIew
`
`Iron overload thalassemic cardiomyopathy: Iron
`status assessment and mechanisms of mechanical
`and electrical disturbance due to iron toxicity
`Suree Lekawanvijit MD1,3, Nipon Chattipakorn MD PhD2,3
`
`s lekawanvijit, n Chattipakorn. iron overload thalassemic
`cardiomyopathy: iron status assessment and mechanisms of
`mechanical and electrical disturbance due to iron toxicity. Can J
`Cardiol 2009;25(4):213-218.
`
`Patients with thalassemia major have inevitably suffered from complica-
`tions of the disease, due to iron overload. Among such complications,
`cardiomyopathy is the leading cause of morbidity and mortality (63.6% to
`71%). The major causes of death in this group of patients are congestive
`heart failure and fatal cardiac tachyarrhythmias leading to sudden cardiac
`death. The free radical-mediated pathway is the principal mechanism of
`iron toxicity. The consequent series of events caused by iron overload lead
`to catastrophic cardiac effects. The authors review the electrophysiological
`and molecular mechanisms, pathophysiology and correlated clinical
`insight of heart failure and arrhythmias in iron overload thalassemic car-
`diomyopathy.
`
`Key Words: Cardiomyopathy; Cardiovascular death; Iron overload;
`Thalassemia
`
`Thalassemia is the most common monogenic disorder causing
`
`decreased globin, a protein composition of hemoglobin synthesis.
`By clinical manifestation, beta-thalassemia major (TM) is the most
`severe form apart from hemoglobin Bart’s disease, which is always
`fatal. TM patients require intensive blood transfusions due to severe
`anemia from ineffective erythropoiesis. Generally, an increase in body
`iron burden occurs in patients who are not receiving transfusions,
`ranging from 2 g to 5 g/year, compared with 0.0015 g/year in healthy
`individuals (1). Regular transfusions may double this rate of iron accu-
`mulation (2). Hence, the inevitably pursuant complications are from
`iron excess in various organs such as the heart, liver and pancreas.
`Although the heart is not the first target organ, cardiac iron overload
`or iron overload cardiomyopathy is regarded as the most serious condi-
`tion (3,4). In the present review, clinical manifestation of iron over-
`load thalassemic cardiomyopathy and the tools used for its detection
`and monitoring are presented. Mechanisms by which iron toxicity
`causes alterations in cardiomyocytes and cardiac electrophysiology are
`also reviewed and discussed.
`
`CliniCal insight
`The incidence of iron overload cardiomyopathy ranges from 11.4%
`to 15.1% in TM (3,5). Usually it begins at an accumulation of 20 g
`of iron (6). In the early stage, patients are usually asymptomatic.
`Restrictive cardiomyopathy usually occurs before dilated cardiomyo-
`pathy (7), in accordance with diastolic dysfunction, which normally
`happens before systolic dysfunction and overt heart failure (8-12).
`
`la myocardiopathie thalassémique par surcharge
`en fer : l’évaluation de la quantité de fer et des
`mécanismes de perturbation mécanique et
`électrique causés par la toxicité ferreuse
`
`Les patients atteints de thalassémie majeure ont inévitablement souffert de
`complications de la maladie en raison d’une surcharge en fer. Parmi ces
`complications, la myocardiopathie est la principale cause de morbidité et
`de mortalité (63,6 % à 71 %). Les principales causes de décès au sein de ce
`groupe de patients sont l’insuffisance cardiaque congestive et les
`tachyarythmies cardiaques fatales. La voie à médiation par radicaux libres
`est le principal mécanisme de toxicité ferreuse. La série d’événements
`causés par la surcharge en fer a des effets cardiaques catastrophiques. Les
`auteurs ont examiné les mécanismes électrophysiologiques et moléculaires,
`la physiopathologie et les aperçus cliniques connexes d’insuffisance
`cardiaque et d’arythmie en cas de myocardiopathie thalassémique par
`surcharge en fer.
`
`Generally, once the onset of a failing heart occurs, the survival time
`is usually less than three months if left untreated (13). Autopsy
`examinations have found dilated cardiomegaly in patients who died
`from late-stage iron overload cardiomyopathy (7). Although systolic
`dysfunction becomes obvious during the late stage, decreased con-
`tractile function has been demonstrated during the early stage of the
`disease (14-16). Left-sided heart failure is clinically more common
`than right-sided heart failure (12). However, it has been shown that
`right ventricular dysfunction develops earlier in asymptomatic TM
`patients (9,17).
`In addition to congestive heart failure, another major cause of
`death in this group of patients is cardiac tachyarrhythmias, which may
`occur simultaneously with a failing heart, leading to sudden cardiac
`death (12). Kremastinos et al (12) reported that the incidence of sud-
`den death was approximately 11.6% in TM patients with left ven-
`tricular failure, which accounted for approximately 18.5% of total
`cardiac deaths. Similar to mechanical dysfunction, electrophysiologi-
`cal dysfunction varies with the stage of disease. Findings in the early
`stage are usually accidental, including bradycardia, ST-T changes,
`infrequent premature atrial or ventricular contractions, first-degree
`atrioventricular block and evidence of left ventricular hypertrophy
`(18,19). In the late stage, frequent premature atrial or ventricular
`contractions, short runs of supraventricular tachycardia, atrial flutter
`and fibrillation, ventricular tachycardia and second-degree or com-
`plete heart block (including intraventricular block) have been dem-
`onstrated (7,12,19). Among these late electrocardiogram (ECG)
`
`1Department of Pathology; 2Department of Physiology; 3Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai
`University, Chiang Mai, Thailand
`Correspondence: Dr Nipon Chattipakorn, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University,
`Chiang Mai 50200, Thailand. Telephone 66-53-945-329, fax 66-53-945-368, e-mail nchattip@mail.med.med.ac.th
`Received for publication November 1, 2006. Accepted March 4, 2007
`
`Can J Cardiol Vol 25 No 4 April 2009
`
`©2009 Pulsus Group Inc. All rights reserved
`
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`Lekawanvijit and Chattipakorn
`
`changes, frequent premature ventricular contraction is most com-
`monly found, while sustained ventricular tachycardia is predominantly
`related to cardiac death (12). Iron levels in the myocardium seem to
`be associated more with arrhythmias and conduction disturbance than
`with the conduction system itself (20,21). It has been shown that
`patients with supraventricular arrhythmias have extensive iron depo-
`sition in the atria, and not in the sinoatrial node (20). In addition,
`patients with atrioventricular block did not have iron deposition in
`the ventricular conduction system (20).
`
`assessment and marKers of
`CardiaC iron status
`Because chelation therapy is an effective way of preventing iron over-
`load cardiomyopathy, the methods and/or markers that can accurately
`assess cardiac iron status and predict the development of cardiac com-
`plications are essential (8,9,11,12,15,16,22-26). Many methods and
`parameters, both direct and indirect, have been investigated. Some
`have been proven to be nonreproducible, some controversial but still
`used, and others are undergoing investigations or being used for
`research work.
`Among serum iron markers, serum ferritin is most commonly used
`as an indirect estimate of body iron store. However, reliance on ferri-
`tin alone can lead to an inaccurate assessment (24). Certain condi-
`tions, such as inflammation, infection and chronic liver disease from
`the hepatitis C virus, which are common complications of thalas-
`semia, may cause an elevation of serum ferritin (27). In view of cardiac
`complications, serum ferritin concentrations have been shown to cor-
`relate poorly with all stages of cardiac dysfunction (diastolic, systolic
`and overt heart failure) (15). Non-transferrin-bound iron (NTBI)
`seems to be the best parameter among serum iron markers. Currently,
`however, it is commonly used only in research studies. Various meth-
`ods and protocols used in the determination of NTBI have been pro-
`posed, but no consensus has been established (28-32).
`Transfusional iron load or the number of blood transfusions is usu-
`ally unreliable in predicting cardiac iron status (25). However, in the
`case of accurate data collection, an increased ratio of the transfusional
`iron load to deferoxamine use (not transfusional iron load alone) has
`been shown to correlate with cardiac dysfunction and death (25).
`Hepatic iron concentration provides the most quantitative
`means of assessing the body iron burden in TM patients (33).
`However, no relationships between hepatic iron concentration and
`cardiac iron status or cardiac dysfunction, have been found
`(16,26,34). Despite being a direct estimation, endomyocardial
`biopsy has not been correlated with cardiac iron status and function,
`possibly due to the pattern of iron deposition and the large sampling
`variation (35). Iron usually deposits primarily in the subepicardial
`layer toward the subendocardial layer and is often patchy (20,36). It
`tends to accumulate in myocardium (especially interventricular sep-
`tum and ventricular free wall) more often than in the conduction
`system. Moreover, clinically, antemortem arrhythmias and conduc-
`tion disturbance have shown no correlation with iron density in the
`conduction system (21). Other assessments, such as antioxidant
`levels – particularly vitamin E, which combats oxidative stress from
`iron toxicity – have been proposed as being indicative of iron over-
`load cardiomyopathy in TM patients (37).
`
`assessment for the development of
`iron overload Cardiomyopathy
`Accurate assessments of cardiac dysfunction and/or cardiac iron sta-
`tus are currently based on imaging techniques. The T2-star magnetic
`resonance (MR-T2*), a novel tool, has been demonstrated to evalu-
`ate cardiac iron status accurately and detect an early global ventricu-
`lar dysfunction (16). In addition, it can be used for monitoring
`myocardial iron levels during iron chelation therapy (22). While
`conventional standard echocardiographic measurements usually
`demonstrate positive findings at the late stage (38), low-dose
`
`214
`
` dobutamine stress echocardiography may be useful for early detection
`of cardiac dysfunction in patients at risk for cardiac hemosiderosis
`(11). Recently, tissue Doppler echocardiography (8) and radionuclide
`angiography (with exercise or low-dose dobutamine stimulation) (9)
`have been shown to detect regional wall motion abnormality, even in
`early-stage thalassemic patients. This finding may also reflect patchy,
`nonhomogeneous deposition of iron in cardiac muscle. However,
`stress echocardiography, tissue Doppler echocardiography and radio-
`nuclide angiography cannot estimate cardiac iron content. MR-T2*
`seems to be superlative (but costly) in terms of noninvasiveness, ear-
`liness (sensitivity) and accuracy (specificity), due to its ability to
`simultaneously assess both cardiac iron and structure, as well as car-
`diac function.
`Although cardiac dysfunction is more clinically obvious than con-
`duction disturbance or arrhythmias in iron-overloaded patients, the
`pathogenesis of arrhythmias may start at the same time, with, or even
`earlier, than contractile dysfunction (39). It has been shown that
`when patients have symptoms of arrhythmias, the mortality rate is
`potentially high (12). Thus, any method or parameter that can deter-
`mine arrhythmogenic risk would be a very useful tool as a guide for
`future therapeutic strategies. Although ECG findings, including 24 h
`Holter monitoring, during the early stage of the disease may trigger
`awareness, they are not specific to iron overload cardiomyopathy.
`Another ECG parameter, QT dispersion, has been proposed to be a
`relevant parameter for the heterogeneity of iron deposition and dura-
`tion of cardiac action potential (23). Kuryshev et al (23) found that
`14 of 24 TM patients with iron overload had increased QT dispersion
`(longer than 60 ms) in their preliminary study.
`Abnormal neurohormonal regulation has been investigated and
`proposed to be a potential contributor to cardiac disease in TM
`patients. Altered sympathovagal balance in TM patients was first
`demonstrated by Veglio et al (18). They investigated heart rate vari-
`ability (HRV) and blood pressure variability in nine asymptomatic
`TM patients and found diminished sympathetic activity. This was
`characterized by the lack of a circadian rhythm of blood pressure and
`heart rate; decreased short-term variability of blood pressure and
`heart rate, particularly at a low frequency range; reduced low to high
`frequency ratio of HRV, suggesting an impaired sympathovagal bal-
`ance; impaired baroreflex gain during a head tilt; and significantly
`decreased plasma norepinephrine. A recent study in iron-overloaded
`rats (40) demonstrated similar findings on baroreflex function.
`Moreover, Franzoni et al (41) demonstrated a significant reduction of
`HRV parameters and increased incidence of ventricular late potential
`(VLP) in asymptomatic TM patients (n=19). In this study, TM
`patients with VLP showed a higher incidence of premature ventricu-
`lar contraction, with episodes of nonsustained ventricular tachycar-
`dia. Recently, De Chiara et al (9) reported that decreased HRV
`parameters can be detected as early as ventricular regional wall
`motion in asymptomatic TM patients (n=20). However, no long-
`term follow-up study has been reported to confirm the validity of
`HRV parameters for predicting cardiac dysfunction and mortality in
`iron overload thalassemic patients.
`In TM patients, renin-angiotensin activity has been shown to
`increase (40). An increased atrial natriuretic peptide level has also been
`proposed as a predictor in asymptomatic TM patients, because it was
`found to be in close correlation with left ventricular diastolic dysfunc-
`tion (42). Taken together, impaired sympathovagal balance and altered
`hormonal regulation may be responsible for the pathophysiology of TM
`patients, who are at risk for iron overload cardiomyopathy.
`
`meChanisms of iron toxiCity
`free radical-mediated iron toxicity
`Tissue toxicity by iron occurs via the free radical-mediated pathway.
`Iron has the capacity to accept and donate electrons, switching
`between Fe2+ and Fe3+, which is known as redox activity. In general, it
`is physiologically essential and present in the plasma in a transferrin-
`bound form. In chronic iron overload, when transferrin is completely
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`saturated, NTBI is found in the plasma (43), which is the form of iron
`that causes toxicity. Iron excess in various conditions is harmful by
`engaging in the Fenton-catalyzed Haber-Weiss reaction to yield
`hydroxyl radicals from hydrogen peroxide and superoxide (44). They
`are all called oxygen free radicals. Highly reactive hydroxyl radical
`production, previously demonstrated in an in vivo model of
`iron-overloaded rats (45), is capable of widespread damage to cellular
`lipids, proteins, sugar and DNA (46).
`
`pathways of iron entry into cardiomyocytes
`In in vitro studies using iron-treated, cultured neonatal rat ventricular
`myocytes (NRVMs), NTBI had more than a 300-fold higher rate of
`uptake than transferrin-bound iron (47). The enhancing rate of NTBI
`uptake occurs in a dose- and time-dependent pattern (34), suggesting
`a carrier- or channel-mediated pathway.
`The exact iron uptake pathway is still unclear. The redox form of
`iron uptake is most likely specific to the reduced Fe2+ form, but not
`Fe3+ (48,49). Using the isolated adult rat heart to study iron uptake,
`Tsushima et al (49) demonstrated that iron uptake was diminished
`when cardiac electrical activity was arrested by potassium chloride.
`This finding suggests that iron uptake partly depends on membrane
`potential, indicating that iron enters the cell via voltage-gated chan-
`nels. Many studies have indicated that the sarcolemmal L-type Ca2+
`channel is a major pathway of iron uptake into cardiomyocytes
`(49-51). Using the patch clamp technique, it has been shown that the
`iron current competes with the calcium current, and is inhibited by a
`calcium channel blocker (49). Other in vivo (chronically iron-loaded
`adult mice) studies have demonstrated the inhibitory effect of L-type
`Ca2+ channel blockers on cardiac iron uptake, indicated by decreased
`tissue iron content (50,51), preserved cardiac function and improved
`survival (51). However, using iron-loaded cultured NRVMs, Parkes
`et al (48) demonstrated contradictory results. They reported that iron
`uptake did not occur via the L-type Ca2+ channel, but was preferably
`dependent on the altered redox (Fe2+ to Fe3+) pathway situated on the
`plasma membrane. The discrepancy in these findings may be due to
`differences in the age of animal models. Neonatal myocytes have
`fewer L-type Ca2+ channels with a smaller L-type Ca2+ current than
`adult myocytes (52). It has been proposed that the Ca2+ current inves-
`tigated in cultured neonatal myocytes may be underestimated due to
`less density in beating cells and more myocyte death (52).
`
`evidenCe of iron-mediated
`CardiomyoCyte damage
`In chronic iron overload, iron toxicity is dose-dependent (53). The
`highly toxic hydroxyl radicals, produced via the Fenton-catalyzed
`Haber-Weiss reaction in the setting of iron excess, is well known to
`damage the lipid-rich cell membrane, which is called lipid peroxida-
`tion, or lipoperoxidation. Lipid peroxidation in the presence of ade-
`quate lipids (substrate) and iron (catalyst) seems to be perpetual. This
`reaction is not only restricted to cell membrane phospholipids, but
`also to other membrane-bound cellular organelles. By studying iron
`overload in cultured NRVMs, Link et al (54) demonstrated evidence
`of lipid peroxidation, reduction in polyunsaturated fatty acids (PUFAs)
`and increased products from cellular lipid peroxidation, particularly
`toxic aldehydes (47,53,55,56). The aldehyde products such as malon-
`dialdehyde and 4-hydroxynonenal can form a covalent link to pro-
`teins (aldehyde-protein adducts), rendering the loss of cellular protein
`function (57).
`Loss of cell membrane integrity from lipid peroxidation was
`evidenced by lactate dehydrogenase release (58). As a result, struc-
`tures located on the cell membrane, such as Na+-K+ ATPase and
`5′-nucleotidase, were affected thereafter (59). Oxidative stress-
`mediated iron tocixity also affects other cellular organelles and their
`functions, such as increased lysosomal fragility (60), decreased mito-
`chondrial inner membrane respiratory enzyme activity and ATP (61),
`decreased protective antioxidant enzyme (ie, glutathione peroxidase)
`
`Can J Cardiol Vol 25 No 4 April 2009
`
`Thalassemic cardiomyopathy
`
`activity, decreased myofibrile elements and a decreased number of
`mitochondria (36).
`
`meChanisms of meChaniCal
`disturbanCe in iron overload
`Cardiomyopathy
`Cardiac effects following iron-induced membrane lipid peroxidation
`can be divided into two parts – changes following altered membrane
`lipid components and their metabolites, and changes following altered
`embedding enzymes, ion channels, receptors and other membrane
`proteins. Arachidonic acid (AA) is a 20-carbon PUFA normally
`esterified in membrane phospholipids. It is released through the action
`of cellular phospholipases, which may be activated by chemical stimuli
`or other mediators. AA metabolites, also called eicosanoids, are lipid
`mediators involved in the signal transduction pathway. Both AA and
`eicosanoids have been shown to play a role in iron overload cardio-
`myopathy (62). In cultured NRVMs treated with iron, Mattera et al
`(62) have shown that the rate of AA release is increased, particularly
`after the angiotensin II type I receptor has been activated. AA has
`been shown to activate mitogen-activated protein kinase (63) and
`apoptosis (64). Because the activated angiotensin II type I receptor is
`associated with cardiomyocyte growth and hypertrophy (65,66), the
`outweighing increment of AA release may be a possible mechanism in
`the progression of cardiac hypertrophy to heart failure in iron overload
`cardiomyopathy (62). In addition, cyclooxygenase-2 (COX-2) activ-
`ity also increased and may be responsible for heart failure development
`in iron overload; it is associated with an increased apoptotic rate and
`symptomatic heart failure (67,68).
`Other than the effects of membrane lipid peroxidation causing cel-
`lular environmental changes, the membrane-embedding enzymes, such
`as Na+-K+ ATPase, Ca2+ ATPase and 5′-nucleotidase, may be attacked
`directly by oxygen radicals (59,69,70). It has been shown that modifica-
`tion of the sulfhydryl groups of these enzymes by an oxygen radical
`reduces their activity (70). Alteration of sarcolemmal Na+-K+ ATPase
`activity in an iron-overloaded heart may be one of the important
`mechanisms in the pathophysiology of the disease. A decrease in
`Na+-K+ ATPase activity was shown in both an iron-loading NRVMs
`(59) and a hydroxyl radical-exposed heart (69). Impaired Na+-K+
`ATPase activity renders an increased resting membrane potential
`(membrane depolarization) and changes in ion conductance. Altered
`Na+-Ca2+ exchange can occur following impaired Na+-K+ ATPase
`activity. An increase in intracellular Na+, due to an impaired Na+-K+
`ATPase pump, shifts the Na+ efflux via Na+-Ca2+ exchange, resulting in
`Ca2+ influx. This Ca2+ influx may persist due to impaired Ca2+ extrusion
`caused by iron-inhibited sarcolemmal Ca2+ pump activity and may lead
`to cardiac arrhythmias (70). Furthermore, Ca2+ influx normally causes a
`release of Ca2+ from the sarcoplasmic reticulum (SR), leading to myo-
`cardial contraction. However, iron (Fe2+) itself has a direct inhibitory
`action on ryanodine-sensitive Ca2+ channels on the SR by competing
`with Ca2+, thus contributing to a reduction in Ca2+-induced Ca2+
`release from the SR (71) results in impaired contractility. Oxygen free
`radicals also have a direct effect on decreased cardiac SR Ca2+ ATPase
`activity (72), which may be responsible for diastolic failure. In the
`in vitro study by Zeitz et al (69), hydroxyl radical-exposed rabbit heart
`muscle was demonstrated to have calcium overload (via Na+-Ca2+
`exchange), with an acute diastolic dysfunction. These mechanisms may
`explain the pathophysiology of early cardiac dysfunction in iron over-
`load cardiomyopathy.
`Persistently high iron and free radicals from iron overload also
`affect other cellular constituents, such as altered function (73), struc-
`ture and number of mitochondria (36,74), altered SR function and
`structure, and decreased myofibril elements (36). Mitochondrial dys-
`function results in decreased phospholipid synthesis of all cellular
`membranes, including the mitochondria themselves (75). SR mem-
`brane destruction from lipid peroxidation, together with impaired
`phospholipid synthesis, leads to calcium leakage into the cytoplasm.
`
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`Lekawanvijit and Chattipakorn
`
`Further increaseses in intracellular calcium can cause degradation of
`membrane phospholipids by activating endogenous phospholipase and
`the degradation of myofibril elements by activating proteases (76).
`The net effect is toward the end stage of cellular declination, eventu-
`ally leading to systolic dysfunction.
`
`meChanisms of eleCtriCal disturbanCe
`in iron overload Cardiomyopathy
`In ex vivo guinea pig hearts, delayed and blocked electrical conduction
`has been demonstrated to occur earlier in iron-loaded cardiac toxicity
`than impaired contractility (39). An optical mapping study of iron-
`loaded Mongolian gerbils (77) also exhibited pertinent results of slow
`conduction and impulse block, with evidence of re-entry, which may
`lead to cardiac arrhythmias. Iron-overloaded cardiomyocytes have been
`shown to have a smaller overshoot potential and a shorter action poten-
`tial duration than iron-free cardiomyocytes in the same heart (23,58).
`An alteration of ion currents characterized by reduced Na+ currents may
`be an underlying mechanism (23). The severity of Na+ current reduc-
`tion is also associated with higher dose and longer duration of iron
`exposure (23). Reduced overshoot potential ensues as a result of
`decreased rapid phase 0 depolarization (fast sodium current). A reduc-
`tion in the late fast sodium current during the plateau phase may result
`in the rapid shortening of the action potential duration due to the dis-
`turbance of a delicate balance of small currents. Abnormal sodium cur-
`rents may also explain the delayed impulse conduction causing widening
`of the QRS complex, as demonstrated in the intact gerbil heart model
`(77). These electrophysiological heterogeneities, including the patchy
`nature of cardiac iron deposition, may provide substrates for re-entry
`and risk of developing fatal arrhythmias (77). Other arrhythmias
`include PR and QRS interval prolongation (65) and bradycardia in the
`early stage (34,66), and premature ventricular contraction (40), ST-T
`changes (66), QT prolongation (66), second- and third-degree atrio-
`ventricular block (65), and arrhythmias in the late stage (59). These
`changes are similar to those reported in iron overload patients (7,19).
`Further investigations on alterations of ion channels, both quantita-
`tively and structurally, are required to explain the association of molecu-
`lar and electrophysiological changes at the cellular level.
`Changes in calcium homeostasis, as described in the ‘Mechanisms
`of Mechanical Disturbance in Iron Overload Cardiomyopathy’ sec-
`tion, may also lead to cardiac arrhythmias, such as triggered activity
`and sudden cardiac death (78). In addition, increased COX-2 activity,
`due to iron overload, results in enhanced eicosanoid production and
`an altered ratio of eicosanoid products (62). An increased ratio of
`prostaglandin E2 to prostacyclin found in an iron overload condition
`can trigger tachyarrhythmias (79,80). This phenomenon can also
`occur when being stimulated by interleukin-1 alpha, an inflammatory
`cytokine (62). Interleukin-1 alpha-related eicosanoid production
`causing fatal arrhythmias may be a hidden mechanism responsible for
`sudden cardiac death in iron overload thalassemic patients, who die
`suddenly from overwhelming infection (7).
`
`possible future therapeutiC
`modalities
`Iron chelation therapy is accepted worldwide as the most effective
`treatment for iron overload cardiomyopathy. In some cases, iron
`chelation therapy is not suitable due to its high cost, poor compliance
`(because of the route of drug administration) and some adverse effects.
`Calcium channel blockers may be useful in preventing NTBI from
`entering cardiomyocytes via the L-type Ca2+ channel (49-51). Oudit
`et al (51) demonstrated that amlodipine and verapamil reduced intra-
`cellular iron accumulation and oxidative stress without disturbing
`diastolic and systolic function. L-type Ca2+ channel blockers affect
`not only cardiomyocytes, but also pancreatic beta cells and anterior
`pituitary cells, which are important target cells for iron toxicity (52).
`On the other hand, because the pathophysiology of iron overload
` cardiomyopathy depends mainly on oxidative injury, antioxidant
`
`216
`
` therapy is possibly one of the best alternative choices. Vitamin E has
`been demonstrated to be effective for this therapeutic purpose
`(37,54,55). However, vitamin C is not useful because it can promote
`iron toxicity by reducing iron redox status (Fe3+ to Fe2+) and enhanc-
`ing cellular uptake, which may worsen cardiac dysfunction in patients
`at risk for iron overload cardiomyopathy (55).
`Omega-3 PUFAs, abundant in fish oil, have been known for their
`cardioprotective effects (81). Although they are substrates in lipid
`peroxidation, the by-products of lipid peroxidation were not increased
`after omega-3 PUFA supplement (82). However, in intensive oxida-
`tive stress due to iron overload, omega-3 fatty acid dietary supplement
`should be used with caution, unless the antioxidant level is adequate
`(83). Using selective COX-2 inhibitors when an anti-inflammatory
`drug is required in these patients may be beneficial in reducing the
`proarrhythmic effect of the eicosanoid product (prostaglandin E2)
`(62). Further studies of COX-2 inhibitor treatment in iron overload
`cardiomyopathy may be worthwhile.
`Natural products have played a role as alternative therapeutic
`modalities in many diseases, including iron overload thalassemia.
`Curcumin, a constitutent of a type of spice, has been demonstrated to
`have antioxidative (84,85), anti-inflammatory (84) and iron-chelating
`effects (86). These beneficial effects may provide vast benefits to iron
`overload TM patients. However, more interventional studies in ani-
`mal models and humans are needed to confirm their beneficial role in
`iron-overload thalassemic cardiomyopathy.
`
`ConClusion
`The most common cause of morbidity and mortality in TM patients is
`iron overload cardiomyopathy, in which the exact pathophysiology is
`crucial for proper management. NTBI has been accepted as the key
`culprit. Recently, the L-type calcium channel was strongly proposed as
`the pathway of intracellular NTBI uptake in cardiomyocytes.
`Subsequent cellular damage occurs mainly via the free radical-mediated
`mechanism, in which iron acts as a catalytic agent. Lipid peroxidation
`seems to play the most important role for both heart failure and
`arrhythmias, particularly by destroying membrane-embedding enzymes
`(such as ATPase) and being the source of AA metabolites.
`For clinical management, early detection is the goal in asymptom-
`atic patients. Cardiac MR-T2*, tissue Doppler echocardiography,
`radionuclide angiography and stress echocardiography are useful imag-
`ing studies for detecting early cardiac dysfunction. Similarly, many
`electrophysiological parameters, such as decreased HRV, presence of
`VLP and impaired baroreflex function, seem to be excellent predic-
`tors, especially for arrhythmias. In addition, several electrophysiologi-
`cal parameters that have been documented as risk stratifiers of other
`cardiovascular diseases (ie, heart rate turbulence) may be applied to
`iron overload cardiomyopathy. Future investigations of large popula-
`tions with long-term follow-up are needed to warrant the clinical
`benefits in iron overload cardiomyopathy.
`
`funding: This work is supported by the Thailand Research Fund
`grant RMU 4980001 (NC).
`
`referenCes
`1. Pippard MJ, Callender ST, Warner GT, Weatherall DJ. Iron
`absorption and loading in beta-thalassaemia intermedia. Lancet
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