.~
`
`r··
`~ ~\ NIH Public Access
`~
`· EJJ Author Manuscript
`0/:-HEP..~ Ann A 1 .·faad Sci . .\uthor manuscript available in P].·!C 20 lO Juo..:: 28.
`Published in final edited form as.
`Ann NY Acad 9j, 2005 ; 1054: 386-395. doi:lO.l 196/annals.1345.047.
`
`Physiology and Pathophysiology of Iron Cardiomyopathy in
`Thalassemia
`
`JOHN c. woooa,b, CATHLEEN ENRIQUEZa, NILESH GHUGREa,b, MAYA OTTO(cid:173)
`DUESSELb, MICHELLEAGUILARb, MARVIN D. NELSONb, REX MOATsb, and THOMAS D.
`COATESc
`llOivision of Pediatric Cardiology, Childrehs Hospital of Los Angeles, Los Angeles, California 90027,
`USA
`
`bOepartment of Pediatric Radiology! Childrens Hospital of Los Angeles, Los Angeles, California
`90027, USA
`
`coivision of Pediatric Hematology, Childrens Hospital of Los Angeles, Los Angeles, California
`90027, USA
`
`Abstract
`Iron cardiomyopathy remains the leading cause-of death in patients with thalassemia major. Magnetic
`n•sonance imaging (:tvfRI) is ideally suited for monitoring thalassemja patients because it can detect
`cardiac iJ.nd Jiv er iron burdens as well as accurately rn easure left ventricular dimensions and function.
`However, patients with thalassernia have unique physiology that alters their normative data. In this
`article, we review the physiology and pathophysiology of thalassemic heart disease as well as the
`use ofMRI to monitor it. Despite regular transfusions, thalassemia major patients have larger
`ventricular volumes, higher cardiac outputs, and lower total vascular resistances than published data
`for healthy control subjects; these hemodynamic findings are consistent with chronic anemia. Cardiac
`iron overload increases the relative risk of further dilation, arrhythmias, and decreased systolic
`function. However, many patients are asymptomatic despite heavy cardiac burdens. We explore ·
`possible mechanisms behind cardiac iron-function relationships and relate these rn echanism s to
`clinical observations.
`
`Keywords
`iron; heart; 1v!RI; ejection fraction; cardiac function; T2*
`
`INTRODUCTION
`
`Tha!assemia, although relatively uncommon in the United States, is the most common genetic
`disease worldwide.1 With increasing East Asian immigration to the Pacific States in the last
`two decades, thalassemia major is becoming an important domestic as well as international
`health challenge. Regular transfusion therapy, while improving patient qualify of life, creates
`a state of iron overload, a second devastating disease. Once reticuloendothelial stores saturate,
`iron deposition increases in parenchymal tissues such as endocrine glands, hepatocytes, and
`
`© 2005 New York Academy of Sci.ences.
`Address for correspondence: John C. Wood, M.D., Ph.D., Division ofCardiology, Mailstop 34, CbildrensHospital of Los Angeles, 4650
`Sunset Blvd.; Los Angeles, CA 90027. Voice: 323-669-5470; fax: 323-669-731 7.jwood@chla.usc.edu.
`
`Coates
`Thursday, April 26, 2018
`
`Reported by; Elizabeth Borrelli
`CSR 7844, CCRR, CLR
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`myocardium. Typically silent for many years, cardiac iron deposition produces arrhythmias,
`systolic and diastolic dysfunction, and congestive heart failure in the s~cond or third life decade.
`
`The introduction of an effective iron chelation agent, deferoxamine, transformed thalassemia
`management in the 1980s. Administered as a continuous subcutaneous infusion, 8-12 hours
`per day, 5-7 days per week, deferoxamine therapy remains an onerous lifeline for thalassemia
`patients . .Although chelation does prolong length and quality of life for thalassemia patients,
`cardiac toxicity remains the leading cause of death, generally striking patients in their third or
`fourth decade. 2 Chelation noncompliance contributes to these deaths; however, some patients
`die despite apparently adequate liver iron chelation. 3 Conventional cardiac surveillance,
`consisting of annual ECG, Holter, and echocardiogram, has proved remarkably ineffective in
`detecting preclinical cardiac iron overload. Electrocardiogram changes reflect primarily left
`ventricular hypertrophy and nonspecific ST-I wave changes from volume overload.
`Conduction abnormalities, consisting primarily of atrioventricular and bundle-branch block,
`typically present after symptomatic disease. Patients may complain of palpitations as the
`earliest clinical symptom; hence Holter monitoring has merit to document atrial and ventricular
`irritability. Iron toxicity arrhythmias are labile and often automatic rather than reentrant in
`nature, typically presenting with polymorphic atrial and ventricular arrhythmias 4 Although
`iron deposition and scarring does occur in the cardiac conduction system, deposits are not
`correlated with clinical presentation.
`
`Abnormalities of ventricular systolic function on echocardiogram are nearly universal but are
`often not detectable until patients are in overt congestive heart failure. Echocardiographic
`assessment of myocardial function may be confounded by segmental wall motion
`abnormalities. As a result, measurements of resting ejection fraction by radionucleide
`angiography and magnetic resonance imaging (:!v1RI) are more robust than echocardiography
`and are better at recognizing preclinical systolic dysfunction. 5 While systolic dysfunction
`carries a grave prognosis, patients can be "rescued" by continuous deferoxamine
`administration, provided they are willing to comply with several years of this therapy. 5' 6
`
`Although many left ventricular filling abnormalities have been described previously in
`thalassemia,7 most reports have failed to acknowledge the critical role .of chronic anemia. 8
`Thalassemia patients have elevated cardiac output and stroke volumes, leading to elevated
`mitral inflow velocities and shorter "deceleration" times, regardless of cardiac iron status. 8
`Restrictive physiology may be observed in advanced disease but is often accompanied by
`systolic dysfunction or severe pulmonary hypertension.8 Impaired myocardial relaxation,
`common in hypertensive and idiopathic hypertrophic cardiomyopathy, has not been well
`documented in thalassemic cardiomyopathy. 7 While diastolic dysfunction measures have the
`potential for earlier diagnosis of cardiac iron toxicity, standard techniques are confounded by
`sensitivity to the volume overload state (discussed in next section).
`
`NORMAL CARDIAC PHYSIOLOGY IN THALASSEMIA MAJOR
`Some of the limitations of conventional cardiac monitoring can be put in perspective by
`considering the normal cardiac physiology of thalassemia patients. Transfusion therapy was
`initiated in thalassemia major to stop the destructive effects of ineffective erythropoiesis and
`marrow expansion. Typically, this can be achieved by keeping pretransfusion hemoglobin
`levels bet\veen 9 and 10 g/dL, leaving patients with a mild chronic anemia.
`
`Because hemoglobin is responsible for oxygen transport, the body compensates for chronic
`anemia in three important ways. 9 Since oxygen delivery represents the product of cardiac
`output, hemoglobin, and hemoglobin saturation (usually >95% regardless of anemia), the body
`can compensate for low hemoglobin levels by increasing cardiac output. This measure can be
`easily documented through :MRI. Table 1 demonstrates cardiac index (cardiac output indexed
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`Ann NY Acad Sci. Author manuscript; available in PMC 2010 June 28.
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`to body surface area) in 19 patients with thalassemia major compared with historical control
`subj ects. 1 O,ll Cardiac index was increased nearly 69% in the thalassetn ia patients com pared
`with control subjects, comparable to their degree of anemia, resulting in relatively normal
`oxygen delivery.
`
`Increased cardiac index c·an be achieved either by increased ventricular stroke voh:rrne index
`or by increased heart rate. We compared heart rate, cardiac index, cardiac volumes, and.ejection
`fraction measured by MRI with vital signs and hemoglobin levels measured during routine
`blood transfusion visits (Table 1). Average heart rate was comparable to that of age-matched
`control subjects. Ejection fraction was within reference limits, but end-diastolic, end-systolic,
`and stroke-volume indices were elevated compared with those of controls.
`
`Therefore, thalassem ia major represents a chronic, high-output state, produced by volume(cid:173)
`loaded ventricles rather than increased heart rate. To maintain a norm al mean systemic blood
`pressure in the presence of high cardiac output, the body would have to lower the systemic
`vascular resistance. 9 This response, similar to the physiologic compensation observed during
`exercise, occurs through peripheral arteriolar vasodilation and leads to wide pulse pressures
`and low diastolic pressures. Systolic blood pressures were comparable to those of age-matched
`control subjects; however, diastolic pressures were significantly decreased in our thalassemia
`patients (Tab1e 1).
`
`To summarize, the "normal" heart in thalassemia pumps at larger volumes (pre-load) and
`against lower peripheral resistance (afterload) than a normal heart. As a result, the expected
`cardiac parameters for non~iron-overload thalassemia major patients remains poorly
`characterized. Should the ejection fraction be higher, lower, or the same as that in an age- and
`sex-matched healthy volunteer? For now, the question remains unanswered. Understanding
`the normal physiologic baseline is critical to interpreting cardiac tests in these patients and
`understanding their response to pathologic stimuli .
`
`EARLY DETECTION OF IRON CARDIOMYOPATHY
`
`Since cardiac function remains normal until late in the spectrum of iron cardiomyopathy, other
`tools are necessary to anticipate and prevent iron cardiomyopathy. Liver iron provides a good
`index of total body iron stores, and high levels may convey future cardiac risk. 12 Although
`traditionally estimated by biopsy or SQIBD, liver iron level can now be accurately estimated
`using.MR). Iron shortens the MRI relation parameters T2 and T2* (and lengthens R2 and R2 *)
`in a predictable and reproducible manner. These, MRI techniques can be used to assess iron
`levels in the heart as well. Both myocardial T2 and T2* shorten in thalassemia patients. IO,
`13-15 Patients with a normal T2* have normal function, but the relative prevalence of
`myocardial dysfunction and arrhythmias increases with lower T2* (high iron). 10,14- 16
`Ventricular function is impaired in approximately 10% of patients having a T2* of 10 ms but
`nearly 70% for patients having a T2* of 4 ms.16 Like many other biomaikers, such as serum
`cholesterol level, abnormal T2* conveys only a relative risk; many patients with relatively high
`iron burdens are asymptomatic at the time of study. Thepredictive value of abnormalT2* is
`strongly implied but has. not yet been demonstrated.
`
`Although liver iron level has been used as a surrogate for cardiac iron form any years, 12, 17 the
`link between cardiac iron and liver iron is quite complicated. Some patients develop ventricular
`dysfunction despite low liver iron concentrations. In fact, there is little or no correlation
`between cardiac T2* (or cardiac function) and liver iron level in cross-sectional analyses_ Io,
`14,15 This observation raised concerns that cardiac T2* did not reflect cardiac iron level.
`However, recent work in animals indicates that cardiac T2 and cardiac T2* are determined
`primarily by cardiac iron concentration. 18,19 The apparent paradox between cross-sectional
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`Ann NY Acad Sci. Author manuscript; available in PMC 2010 June 2.8.
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`
`and longitudinal studies of liver iron can be understood in the context of organ-specific iron
`transport and elimination.
`
`PATHOPHYSIOLOGY OF IRON CARDIOMYOPATHY
`
`Figure 1 is a schematic illustration of the pathophysiology of iron cardiomyopathy, dividing
`the disease process into iron uptake, iron storage, and iron interactions. Characterization of
`iron transport mechanisms is impmtant because it may represent an independent therapeutic
`target to complement chelation therapy. Iron uptake occurs primarily through uptake of non,-(cid:173)
`transferrin-bound iron (NTBI). 20-23 Both ferric and ferrous ions can be absorbed in tissue
`culture, and there are membrane-bound enzymes that facilitate conversion from one species to
`the other. 20 Dimethyl transferase 1 (DMTl) levels have been implicated in intestinal iron
`transport but have not been definitively linked to cardiac iron. transport.21 L-Type voltage(cid:173)
`dependent channels (L VDCs) appear to mediate murine cardiac iron transport, accounting for
`at least half of cardiac iron uptake. 23 Interestingly, neonatal rat m yocytes do not use L VDCs,
`but it.is unclear whether this represents species or maturational specificity. 20
`
`In cell culture, NTBI uptake can be quite rapid. 22 Preexposure of m yocytes to iron increases
`their uptake rate dramatically, suggesting a positive-feedback regulatory mechanism 22,24
`Clinically, this finding indicates that relatively brief periods of very poor chelator compliance
`might lead to significant cardiac iron deposition in vulnerable individuals. Abnormal cardiac
`T2* is rarely found before the age of 10 years, even in patients with high liver iron
`concentrations. 10 However, the prevalence of abnormal T2* jumps to more than 50% in late
`adolescence and early adulthood, suggesting relatively "precipitous" iron loading. This
`transition corresponds with the most difficult years for chelation compliance, but one cannot
`exclude contributions from developmental factors such as puberty.
`
`Both the level and duration ofNTBI exposure are probably important components of cardiac
`iron uptake The level of NTBI appears to be a function of trartsferrin saturation and the liver's
`ability to buffer and store iron. Jensen and colleagues demonstrated that liver iron levels in
`excess of 19.5 mg/g led to dramatic increases in NTBI or "chelatable" iron in unchelated
`patients with myelodysplasia, 25 suggesting a "saturation" threshold for the liver. In turn, excess
`chelatable iron.was strongly correlated with cardiac iron loading by 1v1RI (signal intensity ratio
`technique). Similar cardiac-risk "thresholds" for liver iron in this range have been suggested
`by the work ofBrittenham 12 and Mariotti.44 Liver diseases, such as cirrhosis, that modify the
`liver's ability to buffer and store iron could also increase vuln:erability to extrahepatic iron
`deposition. 26
`
`Although high liver iron levels probably increase cardiac risk, low levels do not guarantee
`cardiac safety. Chronic exposure to lower levels ofNTBI may be ·sufficient for cardiac iron
`overload. Labile iron species are suppressed during deferoxamine therapy but rebound within
`a few hours of stopping infusion. 27 As a result, the hours per day of deferoxamine therapy may
`be as important to the heart as the grams per day of the drug.
`
`Once NTBI enters the m yocyte, it is rapidly buffered by ferriti.t)., limiting its potential for redox
`damage or other hannful interactions in the cell. 2s-30 Within hours, the ferritin- iron complexes
`begin to appear in intracellular siderosomes for long-tenn storage. Some studies have suggested
`a "last-in, first-out" pattern of iron accessibility 28 Although this supposition is intuitive, these
`studies are limited to relatively short-term observations in tissue culture.
`
`From a magnetic perspective, the "free-iron" species have little effect on.MRI T2 or T2* values
`at physiologic concentrations. Once bound to ferritin, iron produces greater inhomogeneities
`in the magnetic field, leading to detectable changes in T2 and T2*. However, clusters of ferritin
`molecules or their breakdown products, such as are found in siderosomes, produce much larger
`
`Ann N YAcad Sci. Author manuscript; available in PMC 2010 June 28.
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`changes (up to sixfold) in T2 or T2* for the same amount of iron than freely diffusing ferritin
`molecules. 31 Hence, lvfRI is measuring predominantly long-term storage depots of iron rather
`than the functionally active iron. This observation explains why some indiv~duals can have
`massive cardiac iron deposition without cardiac symptoms.
`
`Nonetheless, all buffering systems have limited capacity or can be disrupted by other factors.
`Once this occurs, free iron levels rise within the cell, wreaking havoc through redox reactions,
`gene modulation, and direct interaction with ion channels. 30,32-36 Through the Haber-Weiss
`reaction, iron catalyzes production of free radicals, leading to oxidative membrane damage
`throughout the cell. One membrane target is the siderosomes, increasing their fragility and
`competency. 32,37 This, in turn, could potentially lead to release of additional redox-active iron
`species, setting up the potential for a positive-feedback system. Such a phenomenon may
`explain the -catastrophic hemodynamic collapse seen in some patients.
`
`Other membranes involved include the mitochondrial membranes. Iron is avidly taken up by
`mitochondria_3o, 3s Oxidative phosphorylation is impaired, although the mechanisms of this
`disruption are not completely understood Chr.onic irnpajrrnent of mitochonc:lrial energy
`production causes dilated cardiomyopathy in many diseases and may represent a mechanism
`for the asymptomatic functional abnormalities observed in early iron cardiomyopathy.39
`
`Elevated myocyte iron levels .also lead to alterations in gene expression. 33 V/hether these
`changes represent controlled interactions through iron response elements or nonspecific effects
`from redox damage is unclear. Myocytes appear to tonically suppress fibroblast proliferation,
`but this parac1ine effect is reduced by myocyte iron loading.40 This observation represents one
`potential mechanism for iron-induced cardiac fibrosis in the tha1assemic heart.
`
`Ferrous iron has similar size and charge to that of calcium irons, the major mediator of
`excitation- contraction coupling and a major determinant of the cardiac action potential. Hence
`it is not surprising that iron overload results in arrhythmias and poor cardiac function_ 4,3s,36,
`41 Ferrous iron can directly interact with the ryanodine~sensitive calcium channel in the
`sarcoplasmic reticulum. 34 This channel is responsible for activation of contraction and also
`modulates calcium reuptake in the sarcoplasmic reticulum . Ryanodine channel dysfunction is
`the common denominator for a wide variety of congenital and acquired arrhythmogenic
`cardiomyopathies.42
`
`Intracellular iron also impairs function of membrane-bound fast-sodiwn channels as well as
`delayed-rectifier potassium currents. 36 The form er channels are responsible for the rapid
`upstroke of the cardiac action potentia I. Channel blockage or other interference will slow
`cardiac conduction, broadening the QRS of the EKG36,41 and delayed-action potential spread
`across the myocardium.41 Both calcium and potassium channel modification may be
`responsible forrepolarization abnormalities such as early or delayed afterdepolarizations and
`QTc prolongation. These changes are associated with b.oth triggered ventricular arrhythmias
`and reentrant mechanisms such as t.orsade-de-p.ointes,42
`
`Once arrhythm ias or cardiac dysfunction develops, aggressive chelation must be initiated,
`regardless of the total iron burden. The current standard of care remains continuous
`deferoxamine therapy because it provides a continuous "sink" for free iron species. 5' 6
`Continuous administration also rn ay overcome unfavorable transport kinetics .of deferoxamine
`across the myocyte membrane. Cardiac symptoms typically stabilize in a period of weeks to
`months once the "free" iron levels are consistently suppressed. Sustained recovery, however,
`often necessitates continued therapy for several years, suggesting that cardiac iron stores
`deplete more slowly. 5'6 In fact, it has been demonstrated by MRI that therate of iron elimination
`in the heart is nearly sixfold slower than that in the liver. 15,43 The rate-limiting step in cardiac
`iron excretion is not known but may reflect ferritin turnover.
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`The asymmetry of cardiac iron loading and elimination compared with that in the liver
`effectively weakens or destroys any cross-sectional correJ::ition between liver and cardiac iron
`levels. Thus, an elevated liver iron level has no predictive value for whether the heart is
`currently iron loaded, but it may convey prospective risk for subsequent cardiac iron loading .
`.tv1RI offers a unique tool to prospectively study the interplay between hepatic and extrahepatic
`iron stores.
`
`CONCLUSION
`
`Despite transfusion therapy, thalassemia major represents a chronically anemic condition
`resulting in volume-loaded ventricles and increased peripheral vasodilation. 9 As a result, there
`is a paucity of appropriate normative data for thalassemia patients. The mechanisms and
`kinetics of iron entry and clearance differ markedly in the heart and liver, leading to a
`complicated relationship between the two parameters. 20,22,43 Increased levels of stored iron
`can be detected using MRI and are associated with increased relative risk of poor ventricular
`function. 1o,15
`
`Acknowledgments
`
`This work was rupported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (1 ROI
`HL75592·01Al), the General Clinical Research Center at Childrens Hospital Los Angeks (RR0043-43), Department
`of Pediatrics at diildrens Hospital Los Angeles, and Novartis Pharma AG, Basel, Switzerland.
`
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`35. Link G, Athias P, Grynberg A, et al. Effect ofiron loading on transmembrane potential, contraction,
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`their role in lysosornal disruption. Br. J. Haematol 1980;44:593-603. [PubMed: 7378318]
`38. Link G, Saada A, Pinson A, et al. Mitochondrial respiratory enzymes are a major target ofiron toxicity
`in rat heart cells. J. Lab. Clin. Med 1998;131:466-474. [PubMed: 9605112]
`39. Russell LK, Finck BN, Kelly DP. Mouse models of mitochondrial dysfunction and heart failure. J.
`Mol. Cell. Cardiol 2005;38:81-91. [PubMed: 15643424]
`40. Liu Y, Templeton DM. The effects of cardiac myocytes on interstitial fibroblasts in toxic iron
`overload. Cardiovasc. Toxicol 2001;1:299-308. [PubMed: 12213968]
`41. Laurita KR, Chuck ET, Yang T, et al. Optical mapping reveals conduction slowing and impulse block
`in iron-overload cardiomyopathy. J. Lab. Cji.n. Med 2003;142:83-89. [PubMed 12960954]
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`Med2004;14:61-66. [PubMed: 15030791]
`43. Anderson LJ, Westwood MA, Holden S, et al. Myocardial iron clearance during reversal of siderotic
`cardiomyopathy with intravenous desferrioxamine: a prospective study using T2 * cardiovascular
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`44. Mariotti. E, /mgelucci E, Agostini A, et al. Evaluation of cardiac status in iron loaded thalassernia
`patients following bone marrow transplantation during reduction in body iron burden. Br. J. Haematol
`1998;103:916-921. [PubMed: 9886301]
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`FIGURE 1.
`Uptake, storage, and toxicity of cardiac iron in a myocyte. Fe2+ andFe3+ enter the cell and are
`rapidly buffered and stored (bold arrows). Only stored iron is :MRI active. Toxicity occurs
`when the iron buffering system is overwhelmed.
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`Taro Pharmaceuticals, Ltd.
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`Hemodynamic variables in thalassemia major
`
`TABLE 1
`
`Parameter
`
`Cardiac index (L/minlm2)
`
`Pretransfu