AHA Consensus Statement
`
`Cardiovascular Function and Treatment
`in β-Thalassemia Major
`A Consensus Statement From the American Heart Association
`Endorsed by the Thalassaemia International Federation, European Society of Cardiology Working
`Group on Cardiovascular Magnetic Resonance, and Society for Cardiovascular Magnetic Resonance
`Dudley J. Pennell, MD, FRCP, FAHA, Co-Chair; James E. Udelson, MD, FAHA, Co-Chair;
`Andrew E. Arai, MD, FAHA; Biykem Bozkurt, MD, PhD, FAHA; Alan R. Cohen, MD;
`Renzo Galanello, MD†; Timothy M. Hoffman, MD, FAHA; Michael S. Kiernan, MD;
`Stamatios Lerakis, MD, FAHA; Antonio Piga, MD; John B. Porter, MD; John Malcolm Walker, MD;
`John Wood, MD, PhD; on behalf of the American Heart Association Committee on Heart Failure and
`Transplantation of the Council on Clinical Cardiology and Council on Cardiovascular Radiology and Imaging
`
`Abstract—This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction
`in β-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia
`intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are
`considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial
`siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron
`loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia,
`sideroblastic anemia, and hereditary hemochromatosis.
`Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The
`diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular
`adaptation to chronic anemia in non–cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure,
`enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background
`symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early
`identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac
`T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are
`not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also
`be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single
`absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision.
`Acute decompensated heart failure is a medical emergency and requires urgent consultation with a center with expertise in
`its management. The first principle of management of acute heart failure is control of cardiac toxicity related to free iron
`by urgent commencement of a continuous, uninterrupted infusion of high-dose intravenous deferoxamine, augmented by
`
`†Deceased.
`The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship
`or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete
`and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
`This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on April 4, 2013. A copy of the
`document is available at http://my.americanheart.org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase
`additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com.
`This consensus statement was reviewed and endorsed by the ESC Working Group on Cardiovascular Magnetic Resonance, at the request of the American
`Heart Association. Although there is agreement with the general concepts of this document and confidence in the methodology used by the American Heart
`Association, the ESC Working Group on Cardiovascular Magnetic Resonance may not agree with every identified statement and/or specific wording. This
`document was not published by the ESC Working Group on Cardiovascular Magnetic Resonance and is not considered official ESC policy.
`The American Heart Association requests that this document be cited as follows: Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R,
`Hoffman TM, Kiernan MS, Lerakis S, Piga A, Porter JB, Walker JM, Wood J; on behalf of the American Heart Association Committee on Heart Failure
`and Transplantation of the Council on Clinical Cardiology and Council on Cardiovascular Radiology and Imaging. Cardiovascular function and treatment
`in β-thalassemia major: a consensus statement from the American Heart Association. Circulation. 2013;128:281–308.
`Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines
`development, visit http://my.americanheart.org/statements and select the “Policies and Development” link.
`Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express
`permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright-
`Permission-Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Permissions Request Form” appears on the right side of the page.
`© 2013 American Heart Association, Inc.
`Circulation is available at http://circ.ahajournals.org
`
`DOI: 10.1161/CIR.0b013e31829b2be6
`
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`oral deferiprone. Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or
`inotropes because of the unusual loading conditions in TM.
`The current knowledge on the efficacy of removal of cardiac iron by the 3 commercially available iron chelators is summarized
`for cardiac iron overload without overt cardiac dysfunction. Evidence from well-conducted randomized controlled trials shows
`superior efficacy of deferiprone versus deferoxamine, the superiority of combined deferiprone with deferoxamine versus
`deferoxamine alone, and the equivalence of deferasirox versus deferoxamine. (Circulation. 2013;128:281-308.)
`Key Words: AHA Scientific Statement ◼ CT and MRI ◼ heart failure ◼ other heart failure ◼ other treatment
`◼ thalassemia
`
`1. Introduction
`1.1 Need for Consensus Document
`Heart disease has been the predominant cause of death in
`β-thalassemia major (TM) in cohort studies.1–4 Significant
`advances in the identification and risk stratification of
`patients with myocardial siderosis have occurred since 2001
`with magnetic resonance (MR) technology,5–7 and with this,
`it has been possible to focus on the heart as the target lethal
`organ in TM and tailor chelation treatment and prevention
`accordingly.8–10 There is evidence that this approach has con-
`tributed to the significant reduction in cardiac mortality in
`TM.3,11–14 These advances give room for a consensus docu-
`ment in a rapidly evolving field in both diagnostics and thera-
`peutics. The aim of the present document is to bring together
`broad-ranging cardiological and hematologic experience in
`the heart and heart failure (HF) in TM, summarize how to
`measure cardiac iron and function, identify and treat patients
`at high risk to prevent HF, and diagnose and treat HF. A pri-
`mary premise of this review document is that cardiac disease
`is easier and safer to treat at an early stage rather than a late
`stage when the hazard of death is high. We build on previous,
`more focused summary reviews and consensus statements on
`the heart in TM15–20 and build a consensus of the assessment
`of cardiac function and treatment of HF in TM.
`
`2. Fundamentals of TM and the Heart
`2.1 Iron-Loading Conditions
`
`2.1.1 β-Thalassemia Major
`TM is a genetic condition with severe reduction or absent
`production of the β-globin chain constituent of hemoglobin
`(Hb) A. This results in ineffective erythropoiesis caused by
`an excess of α-globin chains and profound anemia that is
`life-threatening from ≈1 to 2 years of age. Blood transfusions
`are required lifelong; however, the iron load of ≈200 mg per
`unit combined with mildly increased gastrointestinal iron
`uptake related to hepcidin suppression21 increases total body
`iron, which leads to a requirement for lifelong iron chelation
`treatment to prevent or reverse iron-related complications. A
`broad phenotypic characterization of TM is the requirement
`for >8 transfusion events per year (may have multiple units
`at each transfusion) in an adult aged >16 years.22 TM varies
`greatly in frequency around the world, being most prevalent in
`areas with endemic population exposure to malaria (Asia, the
`Middle East, Mediterranean Europe), and this is considered to
`
`have created positive pressure for the accumulation of hemo-
`globin genetic mutations that in heterozygote form provide
`innate resistance to parasitization by plasmodia of red cells.
`In countries with no historical exposure to endemic malaria,
`TM occurs through immigration. Thus, the United States and
`the United Kingdom each have <1000 TM patients, whereas
`Indonesia has many thousands of registered TM patients with
`likely high levels of underreporting.
`
`2.1.2 Thalassemia Intermedia
`The cardiovascular manifestations of thalassemia intermedia
`are beyond the scope of this document but typically include
`a greater propensity to pulmonary hypertension and throm-
`bosis.23,24 In thalassemia intermedia, there is a very variable
`increase in gastrointestinal iron uptake. Patients with thal-
`assemia intermedia generally do not require transfusions to
`maintain the hemoglobin level and form part of the spec-
`trum of non–transfusion-dependent thalassemia, which also
`includes other genotypes, such as some patients with E-β-
`thalassemia and HbH disease. As patients with thalassemia
`intermedia get older, however, they may require transfusions
`to prevent complications, including those in the cardiovascu-
`lar system. This leads to iron loading and an increased require-
`ment for iron chelation.
`
`2.1.3 Sickle Cell Anemia
`The cardiovascular manifestations of sickle cell anemia are
`beyond the scope of this document but typically include
`a greater propensity to sickle cell crisis (severe general-
`ized attacks of pain), as well as pulmonary hypertension,
`thrombosis, and stroke.25 Patients with sickle cell anemia
`are increasingly being transfused to prevent cardiovascular
`complications, which leads to iron loading and an increased
`requirement for iron chelation. Although the risks of extra-
`hepatic iron deposition and organ toxicity are lower in
`sickle cell anemia than in other transfusional anemias, they
`increase proportionally to the duration of chronic transfu-
`sion therapy.
`
`2.1.4 Other Iron-Loading Conditions
`There are other causes of iron overload, including conditions
`such as hereditary hemochromatosis, Diamond-Blackfan
`anemia,
`sideroblastic
`anemia, myelodysplasia,
`and
`α-thalassemia, for which these guidelines are relevant but
`for which the evidence base is lower than for TM. Patients
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`with transfusion-dependent Diamond-Blackfan anemia and
`sideroblastic anemia appear to be at particularly high risk for
`extrahepatic iron deposition and toxicity.
`
`2.2 Aims of Transfusion in TM
`The main aim of blood transfusion in TM, beyond prolonging life,
`is the suppression of ineffective erythropoiesis. To achieve this,
`clinical experience and guidelines26 suggest that maintaining a pre-
`transfusion hemoglobin level of 9 to 10 g/dL with a posttransfu-
`sion hemoglobin level of 13 to 14 g/dL leads to a balance between
`minimization of iron loading and maximization of symptom relief.
`Transfusions reduce the expansion of blood volume seen in chronic
`anemia, which is a driver of increased cardiac index.
`
`2.3 Cause of Death in TM
`Before the introduction of chelation, the most common cause
`of death in TM patients receiving regular transfusions in the
`1960s was HF.27 In the era of deferoxamine iron chelation,
`mortality was postponed considerably, but mortality from car-
`diac iron overload continued to dominate the causes of death,
`accounting for ≈70% of cases.1,2,28,29
`
`2.4 Age at Cardiac Death
`The age of cardiac death in TM depends on a number of fac-
`tors, including access to transfusions and chelation. In trans-
`fused but unchelated patients, the typical age at death was 10
`years, primarily of cardiac causes.30 With the introduction of
`deferoxamine treatment in the late 1970s, the median age of
`survival improved and was strongly dependent on birth cohort.
`In the United Kingdom, by the year 2000, the median age at
`death was 35 years.2 Improvements in survival with deferox-
`amine treatment by later birth cohort have been confirmed in
`other countries.3,31,32
`
`2.5 Frequency of Cardiac Iron Overload
`Samples of TM patients in a number of countries across the
`world have shown cardiac iron overload to be common using
`definitions from T2* cardiovascular magnetic resonance
`(CMR) of severe cardiac iron loading of <10 ms and mild to
`
`Table 1. Frequency of Cardiac Iron Overload
`
`Frequency, %
`
`Sample Size,
`n
`
`Severe:
`T2* <10 ms
`
`Mild to Moderate:
`T2* >10–20 ms
`
`Normal:
`T2* >20 ms
`
`109
`180
`28
`30
`81
`141
`167
`220
`159
`3445
`
`43
`20
`24
`26
`39
`46
`27
`37
`22
`24
`21
`13
`52 (8–20 ms)
`13 (<8 ms)
`30% <20 ms
`68% <20 ms
`22
`
`20
`
`37
`50
`14
`37
`54
`66
`35
`66
`32
`58
`
`Country
`
`United Kingdom5
`Hong Kong33
`Turkey34
`Australia35
`Oman36
`United States37
`Italy38
`Italy39
`Greece40
`Worldwide
`survey41
`
`moderate cardiac iron loading of 10 to 20 ms (refer to Section
`3.3 for measurement of iron by T2* CMR; Table 1).
`
`2.6 Frequency of Cardiomyopathy
`There are 2 ways by which cardiomyopathy prevalence can be
`measured. The first is by prevalence of the clinical syndrome
`of HF. The prevalence varies by patient age and by year of
`birth. In a cohort of 97 patients born before 1976, 37% had
`heart disease, as defined by need for inotropic or antiarrhyth-
`mic medications.28 In a US survey in 2004, the number of TM
`patients of all ages receiving cardiac medication was found
`to be 10% (35/341).22 In an Italian cohort, the prevalence of
`HF by 15 years of age was 5% in patients born between 1970
`and 1974 and 2% in those born between 1980 and 1984.42 In
`a worldwide survey conducted in 2012, the incidence of HF
`at first T2* scan was 3.1% (107/3445).41 Alternatively, the
`prevalence of detectable left ventricular (LV) dysfunction is
`higher than the prevalence of clinically manifest HF. In one
`study of 167 Italian patients, LV dysfunction was found in 19
`patients (11.4%).38 Another more recent Italian study found a
`high prevalence of LV dysfunction of 19%. This higher figure
`may represent the high prevalence of hepatitis C infection43
`and aging of the Italian TM population compared with clinical
`experience elsewhere.
`
`2.7 HF and Survival
`The natural history and clinical course in untreated patients
`is one of clinically silent myocardial iron accumulation for
`many years, followed by malignant arrhythmias and acutely
`impaired myocardial function in early adulthood.27,44 The
`time from symptom appearance to death was short, typically
`approximately 6 to 12 months. With improved access to
`iron chelation in the 1970s, life expectancy improved, with
`patients expected to survive to their mid-30s28,31,45; however,
`5-year survival for patients presenting in HF (ages 24±5
`years) was only 48%.46 These data were disconcerting given
`the ample evidence that intensive iron chelation therapy
`could completely restore cardiac function in most patients
`with preclinical dysfunction and some with overt HF.47–49 The
`clearance of cardiac iron substantially lagged improvements
`in systolic function,47 which explains the high risk of relapse
`observed with premature termination of intensive chelation
`therapy.48,49 Recognition of severe cardiac siderosis by T2*
`CMR and intervention with suitable treatment, before the
`onset of symptomatic HF, is associated with improvements
`in ventricular function.50 As a result, recent improvements in
`life expectancy for TM patients in the United Kingdom can
`be explained by the increasing availability of T2* CMR and
`earlier escalation of therapy.11,51 The acute mortality of New
`York Heart Association stage IV HF in thalassemia remains
`high (probably in excess of 50% in hospital mortality)
`simply because support for the heart and other failing organs,
`especially the kidneys and liver, often cannot be continued long
`enough for iron chelation to stabilize myocardial function,
`a process that may take many months. Nonetheless, futility
`cannot be predicted, and intensive chelation and prolonged
`cardiopulmonary support should be attempted in all patients
`with iron cardiomyopathy, because survival to an excellent
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`quality of life may be achieved in a significant proportion of
`patients.
`
`2.8 Age, Transfusions, and Cardiac Loading
`There are few data relating the age of onset of cardiac iron
`loading with age and transfusion history. Among patients
`with myelodysplasia who received transfusions but no che-
`lation, those with cardiac T2* <20 ms had received >100 U
`of blood.52 In children with hemoglobinopathy who received
`transfusion and chelation, the cardiac T2* was <20 ms only
`after 10 years of age.53,54 However, occasional younger onset
`of cardiac iron, as young as 7 years, has been recorded in TM,
`especially when access to chelation is limited.55
`
`2.9 Cardiac Uptake of Iron
`There is an incomplete understanding of iron loading into the
`heart, and no studies have been performed in humans. Cell
`and animal studies have indicated that cardiac entry of iron
`is mediated by the divalent metal transporter 1 (DMT1) and
`L-type calcium channels,56,57 as well as the T-type calcium
`channels,58 although another pathway may be involved for fer-
`ric (Fe)3+ ions.59 Non–transferrin-bound iron uptake has been
`shown to be rapid in isolated cardiomyocytes.60 Nifedipine
`was shown to hinder iron uptake into cardiac cells, and this
`therapeutic possibility is being explored in a pilot study in
`humans.61 Anecdotal evidence from individual cases62 and
`family studies of discrepant cardiac iron loading, as well as
`evidence from a worldwide survey of cardiac T2*,41 suggests
`that genetic modifiers of cardiac iron uptake may be present
`and clinically relevant. The only genetic influence known to
`date is the glutathione S-transferase-M1 (GSTM1) null gen-
`otype, which was associated with an increased level of car-
`diac iron.63,64 GSTM1 has also been implicated in liver iron
`loading.65
`
`2.10 Cardiac Pathophysiology in TM
`In untreated TM, chronic profound anemia causes high–car-
`diac-output HF and is fatal at a young age. The early start
`of regular transfusion prevents early cardiac death and other
`complications of anemia but results in progressive iron accu-
`mulation toxicity. In the heart, increased levels of intracellu-
`lar free iron are toxic through a number of mechanisms,66,67
`including (1) damage to membranes by lipid peroxidation; (2)
`damage to mitochondria and the respiratory enzyme chain68,69;
`(3) interference with electrical function, including ryanodine
`release channel interference70,71; (4) promotion of cardiac
`fibrosis, which was prominently reported in early autopsy
`studies,72 although it is rare with greater access to chelation73;
`and (5) altered gene expression.74
`
`2.11 Adaptive Cardiac Physiology in TM in Absence
`of Cardiac Iron Loading
`Because hemoglobin is responsible for oxygen transport,
`to preserve oxygen delivery, the body compensates for low
`hemoglobin levels by increasing the cardiac output and car-
`diac index, which is the cardiac output normalized to body sur-
`face area, up to 60% compared with normal control subjects.
`The increased cardiac index is usually achieved by an increase
`
`in end-diastolic volume, stroke volume, and heart rate. TM
`therefore represents a chronic high-output state produced by
`volume-loaded ventricles (high preload). To maintain normal
`systemic blood pressure in the presence of high cardiac out-
`put, the body has to lower the systemic vascular resistance
`through peripheral arterial vasodilation, which leads to wide
`pulse pressures and low diastolic blood pressure.70,75,76 The
`increased cardiac output may lead to flow murmurs on car-
`diac auscultation. The ejection fraction is increased because
`of decreased afterload and increased preload.
`
`2.12 Clinical Cardiac Manifestations of
`Iron Overload
`In the absence of regular iron chelation, historical series show
`a broad range of cardiac complications, including pericarditis,
`myocarditis, HF, and arrhythmias.27,72 In the modern era,
`with iron chelation treatment, the clinical manifestation of
`cardiac disease has changed, and pericarditis and myocarditis
`are now rare. Historical postmortem studies showed severe
`replacement cardiac fibrosis,27,72 but this is now rare in more
`modern cohorts of patients dying of HF.73 More minor patches
`of myocardial fibrosis have been identified in vivo with late
`gadolinium-enhancement CMR in Italian patients with TM,77
`but this has not been reproduced in the United Kingdom.78
`This difference probably results from higher levels of
`myocarditis resulting from hepatitis C infection in Italy.79
`The most common clinical manifestations of cardiac disease
`are now dilated cardiomyopathy (with restrictive features)
`and arrhythmia, predominantly atrial fibrillation (AF). In
`severe cardiac iron loading, ventricular arrhythmias become
`more common, and ectopic atrial tachycardia, flutter, and
`chaotic atrial rhythms may also occur. Recent autopsy data
`show that iron deposition in the myocardium in TM patients
`occurs preferentially in the subepicardium, no systematic
`variation occurs between myocardial regions, and iron in the
`interventricular septum is highly representative of total cardiac
`iron.7 Some authors advocate use of multislice T2* data to
`characterize heterogeneity in myocardial iron distribution, but
`this technique requires corrections for large, patient-specific
`magnetic susceptibility artifacts. Although global sampling
`of cardiac T2* potentially offers a more complete picture of
`cardiac iron burden, anatomic correlations for this approach
`are lacking.39 Other relevant iron-overload complications
`that may affect the heart include hypothyroidism, diabetes
`mellitus, hypoadrenalism, growth hormone deficiency, and
`hypoparathyroidism.
`Changes in the heart in addition to ventricular systolic
`impairment include the following: (1) Decreased left atrial
`function, which is attributable to ventricular stiffening or
`direct atrial toxicity. Limited data suggest that decreased
`left atrial function is a more sensitive marker of iron toxicity
`than left ventricular ejection fraction (LVEF),76,80 but further
`data are needed. (2) Impaired right ventricular (RV) func-
`tion, which may be caused by the increased vulnerability of
`the RV to the effects of iron deposition because of its thin
`wall. Tissue Doppler imaging velocity and strain imaging
`suggest early RV impairment in iron overload.81 (3) Impaired
`endothelial function in iron overload.9,82–84 Improvement in
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`endothelial function has been documented with deferiprone9
`and deferasirox.83 (4) Impaired diastolic function as shown by
`tissue Doppler imaging has been reported with cardiac iron
`overload, but only in small studies, and its low sensitivity lim-
`its its use for diagnosis and as a prognostic tool.85,86 Impaired
`diastolic function shown by CMR also had low sensitivity for
`identification of cardiac iron loading.87
`
`2.13 Vascular Effects of Iron Loading
`Patients with TM and normal cardiac iron levels documented
`by T2* and no clinical signs of cardiac dysfunction have
`increased aortic stiffness as assessed by pulse-wave velocity
`(carotid-femoral) and augmentation index compared with nor-
`mal control subjects.88
`
`3. Diagnostic Strategies for
` Cardiac Involvement in TM
`3.1 Basic Tests
`New-onset electrocardiographic abnormalities are usually
`evident in TM patients with HF89 and may include supraven-
`tricular arrhythmias, electrocardiographic findings that sug-
`gest right-sided heart involvement (S1Q3 pattern and right-axis
`deviation), new-onset T-wave inversion beyond lead V1, and
`a consistent decrease in QRS height. In patients without HF,
`an abnormal ECG was found in 46% (T-wave abnormali-
`ties in 34% and right bundle-branch block in 12%), which
`was weakly associated with lower myocardial T2* and mild
`myocardial fibrosis, probably from hepatitis C myocarditis.90
`Electrocardiographic changes most specifically associated
`with cardiac iron include repolarization abnormalities and
`relative bradycardia.91 It is not known whether progressive
`alterations in electrocardiographic tracings occur before HF
`develops.
`The chest radiograph may show cardiomegaly caused by
`the hyperdynamic circulation, signs of congestive HF, and,
`on occasion, extramedullary hematopoiesis as indicated
`by the lobulated soft tissue opacities of the ribs anteriorly
`and posteriorly. N-terminal pro-B-type natriuretic peptide
`(NT-proBNP) and B-type natriuretic peptide (BNP) are sig-
`nificantly increased in documented LV diastolic dysfunction,
`whereas NT-proBNP appears to have better predictive value
`in detecting latent LV diastolic dysfunction.92 However, one
`study showed poor correlation of BNP against low myocar-
`dial T2*, which predicts future HF.50 One possible explanation
`for this finding is cardiac endocrinopathy and reduced BNP
`secretion caused by iron toxicity. More recent data suggest
`that NT-proBNP levels may be useful,93 and further studies
`are needed.
`
`3.2 Noninvasive Techniques to Measure
`Cardiac Function
`3.2.1 Echocardiography
`A number of factors affect cardiac function measurements by
`different techniques, and this makes comparisons between tech-
`niques and different laboratories difficult.94 Echocardiography
`is a very useful cardiac examination because its application is
`widespread, safe, economical, and routine in clinical practice;
`
`however, image acquisition depends on the operator and the
`availability of good acoustic windows. Reproducibility is
`reasonable in normal ventricles, but the quantification of vol-
`umes and mass relies on geometric assumptions that do not
`apply in ventricles undergoing asymmetrical cardiac remod-
`eling, such as in cardiomyopathy,95 and measurements show
`significant interobserver variability. In a small study of 36
`patients, a resting LVEF <60% by echocardiography corre-
`lated with increased cardiac mortality over a 12-year period.96
`Echocardiography provides less accurate quantification than
`CMR, and accuracy decreases with worsening LV function as
`geometric assumptions lose validity. In addition, typical echo-
`cardiography measurements include the papillary muscles in
`the blood pool, which leads to systematic overestimation of
`volumes. Echocardiography is the preferred second-line tech-
`nique after CMR, and 3-dimensional is preferable to 2-dimen-
`sional because of improved longitudinal reproducibility. It
`is important that echocardiography be performed in experi-
`enced centers that are used to scanning TM patients in large
`numbers. Echocardiography is the easiest way to evaluate the
`diastolic LV function/dysfunction in patients with TM with
`published guidelines.97
`
`3.2.2 Radionuclide Ventriculography
`Radionuclide ventriculography during exercise is reported as
`a sensitive technique for detecting preclinical myocardial dys-
`function in patients with systemic iron overload.98 However,
`its use is limited in the current era because of concerns about
`radiation dose in young people, considerable intercenter vari-
`ation in normal values of ejection fraction related to differ-
`ences in background radiation–subtraction techniques, and the
`availability of other techniques such as echocardiography and
`CMR, which are usually preferred.
`
`3.2.3 Cardiovascular Magnetic Resonance
`CMR is also free of ionizing radiation, noninvasive, and
`highly reliable. In addition, CMR is independent of geometric
`assumptions for assessment of LV volumes and function and
`has been shown to be accurate and reproducible. However, it
`is more expensive than echocardiography, is performed in a
`claustrophobic environment, and is limited in patients with
`cardiac devices (although CMR-compatible devices are now
`available). Despite the special expertise required to perform
`and interpret CMR, it is considered the “gold standard” today
`for the measurement of all LV and RV indexes. With the
`introduction in recent years of the steady-state free precession
`technique with much improved blood-myocardium contrast,
`faster acquisition, and improved temporal resolution of the
`cine images, the image quality is superior to the spoiled
`gradient echo sequences, which are more of a historical issue
`at this point. Steady-state free precession end-expiratory
`breath-hold cines should be acquired in the vertical and
`horizontal long-axis planes, with subsequent contiguous
`short-axis cines from the atrioventricular ring to the apex.
`LV mass should be calculated from the end-diastolic frames
`after the epicardial and endocardial borders of the LV are
`delineated and should include the papillary muscles. End-
`systolic and end-diastolic volumes are best calculated from
`the LV volume-time curves generated from all frames of
`all cines, should exclude the papillary muscles, and should
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` Circulation
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` July 16, 2013
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`model LV blood pool changes from systolic valve descent.
`Such rigorously derived CMR cardiac volumes have the
`benefit of having recognized normalized values for sex, body
`surface area, and age for both the LV99 and the RV.100 These
`covariates have substantial impact on the normal ranges.
`However, many CMR analysis software packages do not have
`this full modeling capability, and in that case, normal values
`appropriate to the software should be used. CMR is more
`reproducible than other techniques over time101,102; therefore,
`it is preferred for follow-up of patients over time when it is
`available. Finally, it is important to compare normal values for
`LV103 and RV104 function with values obtained in nonanemic
`TM patients to prevent misdiagnosis of abnormality, as
`detailed below. Such comparisons are now also available
`for children.105,106 A further value of CMR is related to
`the use of late gadolinium enhancement, which identifies
`myocardial replacement fibrosis. This can be useful to identify
`myocarditis and myocardial infarction, which are uncommon
`differential diagnoses in HF in TM patients.107 CMR with late
`gadolinium enhancement should be considered in any patient
`who has a positive test result for hepatitis C, has abnormal
`cardiac function in the absence of cardiac iron, or has other
`known cardiovascular risk factors, such as chronic diabetes
`mellitus. Diastolic cardiac function is measured in clinical
`practice by echocardiography, and CMR is not generally used
`for this assessment despite the fact that it provides absolute
`peak filling rates from the volume-time curves108 that are
`at higher spatial resolution than provided by radionuclide
`ventriculography. Performance of CMR requires training an