W J C
`
`World Journal of
`Cardiology
`
`Online Submissions: http://www.wjgnet.com/esps/
`wjc@wjgnet.com
`doi:10.4330/wjc.v5.i8.270
`
`World J Cardiol 2013 August 26; 5(8): 270-279
`ISSN 1949-8462 (online)
`© 2013 Baishideng. All rights reserved.
`
`Early detection of cardiac involvement in thalassemia: From
`bench to bedside perspective
`
`REVIEW
`
`Nut Koonrungsesomboon, Siriporn C Chattipakorn, Suthat Fucharoen, Nipon Chattipakorn
`
`Nut Koonrungsesomboon, Siriporn C Chattipakorn, Nipon
`Chattipakorn, Cardiac Electrophysiology Research and Training
`Center, Department of Physiology, Faculty of Medicine, Chiang
`Mai University, Chiang Mai 50200, Thailand
`Nut Koonrungsesomboon, Department of Pharmacology, Fac-
`ulty of Medicine, Chiang Mai University, Chiang Mai 50200,
`Thailand
`Siriporn C Chattipakorn, Department of Oral Biology and Di-
`agnostic Science, Faculty of Dentistry, Chiang Mai University,
`Chiang Mai 50200, Thailand
`Suthat Fucharoen, Thalassemia Research Center, Institute of
`Molecular Medicine, Mahidol University, Bangkok 3310, Thai-
`land
`Author contributions: Koonrungsesomboon N, Chattipakorn
`SC, Fucharoen S and Chattipakorn N solely contributed to this
`paper.
`Supported by Thailand Research Fund grants RTA5580006 and
`BRG5480003
`Correspondence to: Nipon Chattipakorn, MD, PhD, Cardiac
`Electrophysiology Research and Training Center, Department of
`Physiology, Faculty of Medicine, Chiang Mai University, Huay
`Kaew Road, Tambon Suthep, Muang District, Chiang Mai 50200,
`Thailand. nchattip@gmail.com
`Telephone: +66-53-945329 Fax: +66-53-945329
`Received: July 9, 2013 Revised: July 31, 2013
`Accepted: August 5, 2013
`Published online: August 26, 2013
`
`Abstract
`Myocardial siderosis is known as the major cause of
`death in thalassemia major (TM) patients since it can
`lead to iron overload cardiomyopathy. Although this
`condition can be prevented if timely effective intensive
`chelation is given to patients, the mortality rate of iron
`overload cardiomyopathy still remains high due to late
`detection of this condition. Various direct and indirect
`methods of iron assessment, including serum ferritin
`level, echocardiogram, non-transferrin-bound iron,
`cardiac magnetic resonance T2*, heart rate variability,
`and liver biopsy and myocardial biopsy, have been pro-
`
`posed for early detection of cardiac iron overload in TM
`patients. However, controversial evidence and limita-
`tions of their use in clinical practice exist. In this review
`article, all of these iron assessment methods that have
`been proposed or used to directly or indirectly deter-
`mine the cardiac iron status in TM reported from both
`basic and clinical studies are comprehensively sum-
`marized and presented. Since there has been growing
`evidence in the past decades that cardiac magnetic
`resonance imaging as well as cardiac autonomic status
`known as the heart rate variability can provide early
`detection of cardiac involvement in TM patients, these
`two methods are also presented and discussed. The ex-
`isting controversy regarding the assessment of cardiac
`involvement in thalassemia is also discussed.
`
`© 2013 Baishideng. All rights reserved.
`
`Key words: Thalassemia; Iron overload; Cardiomy-
`opathy; Serum ferritin; Heart rate variability; Magnetic
`resonance; Non-transferrin-bound iron
`
`Core tip: The mortality of thalassemia major (TM) pa-
`tients due to iron overload cardiomyopathy is still high
`even though it can be prevented with effective chela-
`tion. The role of reliable methods to determine cardiac
`iron status is very important in order to give a timely
`effective treatment. This review article provides a com-
`prehensive summary and discussion of various iron as-
`sessment methods as well as their existing controversy
`for use from both basic and clinical reports that have
`been proposed or used to directly or indirectly deter-
`mine the cardiac iron status in TM.
`
`Koonrungsesomboon N, Chattipakorn SC, Fucharoen S, Chat-
`tipakorn N. Early detection of cardiac involvement in thalas-
`semia: From bench to bedside perspective. World J Cardiol
`2013; 5(8): 270-279 Available from: URL: http://www.wjg-
`net.com/1949-8462/full/v5/i8/270.htm DOI: http://dx.doi.
`org/10.4330/wjc.v5.i8.270
`
`WJC|www.wjgnet.com
`
`270
`
`August 26, 2013|Volume 5|Issue 8|
`
`Apotex Tech.
`Ex. 2028
`
`

`

`Koonrungsesomboon N et al. Detection of cardiac involvement in thalassemia
`
`INTRODUCTION
`Thalassemia major (TM) is an inherited anemia caused
`by impaired synthesis of the beta goblin chain. The
`prevalence of thalassemia is high in the Mediterranean
`countries, the Middle East, Central Asia, India, Southern
`China and Thailand[1]. Approximately 60000 TM infants
`are reportedly born each year[2]. Due to severe hemolytic
`anemia, TM patients need to habitually receive blood
`transfusions beginning in infancy. Regular blood trans-
`fusions, increased intestinal iron absorption as well as
`the lack of active excretion of iron inevitably lead to an
`excess accumulation of iron in the body of TM patients
`including not only in the reticuloendothelial cells, but
`also in the parenchymal tissues as well[3]. Excess free iron
`participating in the Fenton-type reaction has been shown
`to contribute to the pathogenesis of hemochromatosis[4].
`Among many complications due to iron overload, myo-
`cardial siderosis is the major cause of mortality in these
`TM patients[5].
`At present, although bone marrow transplantation
`has been shown to effectively cure some selected pa-
`tients, the cornerstone of treatment in TM is still with
`blood transfusion and iron chelation therapy. The effec-
`tiveness of iron chelation has markedly improved since
`the introduction of oral chelators, such as deferiprone[6]
`and deferasirox[7], resulting in prolonged life expectancy
`and increased quality of life in TM patients. Despite the
`effectiveness of iron chelators, iron overload cardiomy-
`opathy can be reversible only if early intensive chelation
`has been initiated[8,9]. Once TM patients develop clinical
`symptom such as heart failure or arrhythmia, the prog-
`nosis usually becomes poor and death thereafter in spite
`of intensive chelation[10]. These findings indicate the im-
`portance of early detection of cardiac iron accumulation
`prior to the development of cardiac dysfunction, and that
`the intensive chelation can be given promptly to those pa-
`tients who are at risk. Currently, various methods for the
`detection of cardiac involvement in iron overload condi-
`tion have been reported both in animal models as well as
`in clinical studies. Nevertheless, there are still limitations
`of their use in TM patients due to controversial reports
`on their reliability or limited access to the machine used
`for the detection as well as their high cost. In this review
`article, various methods that have been proposed or used
`to directly or indirectly determine the cardiac iron status
`in TM reported from basic and clinical studies are com-
`prehensively summarized and presented. The existing
`controversy regarding the assessment of cardiac involve-
`ment in thalassemia is also discussed.
`
`ASSESSMENT OF CARDIAC
`INVOLVEMENT IN THALASSEMIA
`Since clinical evaluation is unreliable to detect an early stage
`of iron overload cardiomyopathy in TM patients, several ap-
`proaches have been used to determine cardiac iron status in-
`
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`271
`
`stead. These include the indirect cardiac iron assessment such
`as serum ferritin, echocardiogram, and electrocardiogram
`(ECG) as well as the direct but invasive assessment such
`as myocardial biopsy and liver biopsy. Since there has been
`growing evidence in the past decades that cardiac magnetic
`resonance imaging (MRI) as well as cardiac autonomic status
`known as the heart rate variability (HRV) can provide early
`detection of cardiac involvement in TM patients, these two
`methods will also be presented and discussed.
`
`Serum ferritin
`Serum ferritin has been used for decades as a predic-
`tor of iron overload status in clinical practice due to its
`strong correlation with hepatic iron[11], representing an
`indirect index for estimating the total body iron stores.
`It is inexpensive and accessible worldwide. Serum fer-
`ritin has been shown to have a positive relationship with
`the amount of blood transfusion in beta-thalassemia
`patients[12]. Furthermore, it has been shown that a serum
`ferritin level greater than 1800 μg/L was associated with
`the increased concentration of cardiac iron, and that se-
`rum ferritin greater than 2500 μg/L was associated with
`the increased prevalence of cardiac events[13].
`The downturn of using serum ferritin as an assess-
`ment of iron overload is due to the fact that the increased
`level of serum ferritin is not specific to iron overload con-
`dition since its level can also be increased in other condi-
`tions such as inflammation, collagen diseases, hepatic
`diseases, and malignancy[14]. Evidence indicated that an
`increased serum ferritin levels might be a defense mecha-
`nism of the body against oxidative stress[15]. Moreover, a
`low serum ferritin level does not necessarily designate low
`risk of iron-induced cardiomyopathy[16]. Several studies
`in the last decade demonstrated that serum ferritin is not
`suitable for its use as a predictive indicator of myocardial
`iron deposition due to its lack of relationship with cardiac
`iron[17,18]. A recent study reported that many unexplained
`cardiac deaths in TM patients were found even though
`they had low serum ferritin levels[19], emphasizing the un-
`reliable use of serum ferritin as a predictor for iron over-
`load cardiomyopathy in TM patients.
`
`Echocardiogram
`Echocardiogram is a valuable tool for cardiac function
`monitoring in clinical practice. However, several stud-
`ies demonstrated that it is not sensitive enough for early
`detection of the preclinical stage of cardiac involvement
`in TM patients due to the typical late onset of symptoms
`and signs[20]. Once cardiac dysfunction is detected by an
`echocardiogram, the survival rate of these patients is re-
`duced[21,22], suggesting a late stage detection of the disease
`by this assessment. In addition, it has been shown that
`the absence of a reduced left ventricular ejection fraction
`(LVEF) does not exclude a significant risk of sudden
`potential cardiac decompensation from iron overload[23].
`Since left ventricular function is often slightly higher
`than normal in thalassemia patients in the absence of
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`Koonrungsesomboon N et al. Detection of cardiac involvement in thalassemia
`
`myocardial iron overload[24], the normal values of cardiac
`function by echocardiogram may not be able to rule out
`cardiac impairment by iron deposition in these patients.
`Therefore, routine monitoring of cardiac function by
`echocardiogram is not reliable in early detecting thalas-
`semia patients with high risk of cardiac involvement in
`order to provide timely intensive treatment.
`
`Electrocardiogram
`Since most of TM patients with early cardiac involve-
`ment are asymptomatic, ECG has no value for screening
`of cardiac involvement in this group of patients[25]. Simi-
`lar to echocardiogram, once the development of cardiac
`arrhythmias, such as premature atrial or ventricular con-
`tractions, first-degree atrioventricular block, atrial flutter,
`atrial fibrillation, ventricular tachycardia, and second-de-
`gree or complete heart block[26-28], is detected by ECG, it
`usually implies an advanced stage of disease[29,30]. Further-
`more, a normal ECG does not exclude a risk of signifi-
`cant arrhythmia development in iron overload patients[25].
`In a retrospective analysis, which included 27 transfusion-
`dependent thalassemia patients who underwent annual
`24-h electrocardiographic monitoring, two patients devel-
`oped significant clinical symptoms secondary to cardiac
`arrhythmias within one year of follow-up[31]. This result
`indicated that a 24-h electrocardiogram might be useful
`for arrhythmia detection, but is not totally predictive for
`life-threatening cardiac events. Therefore, both ECG and
`conventional 24-h ECG monitoring are not appropriate
`markers for early detection of cardiac involvement in
`thalassemia patients.
`
`Liver and myocardial biopsy
`Liver biopsy is a direct determination of liver iron con-
`centration closely reflecting total body iron storage[32].
`However, a previous study demonstrated that hepatic
`iron concentration correlates poorly with cardiac iron
`status and cardiac function[33]. These findings indicated
`that determination of iron level via liver biopsy does not
`reflect cardiac iron deposition. Moreover, this technique
`is an invasive procedure that is not suitable for regular
`monitoring of iron status in thalassemia patients.
`A previous study has also shown that iron level deter-
`mined by an invasive myocardial biopsy was not corre-
`lated with cardiac iron status and cardiac function[34]. This
`could be due to the fact that myocardial iron deposition
`was inhomogeneous in the heart[35]. As a result, myocar-
`dial biopsy is not recommended to be used as an indica-
`tor for cardiac iron overload assessment.
`
`Superconducting quantum interference device
`Superconducting quantum interference device (SQUID)
`biomagnetic liver susceptometry (BLS) has become a
`standard method in monitoring iron in the liver[36,37].
`However, it has many limitations including its availability,
`cost, technical demands, and suboptimal reproducibil-
`ity[38]. Together with the lack of heart data, SQUID has
`not been recommended for its use in the evaluation of
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`272
`
`cardiac iron status in patients with thalassemia.
`
`Non-transferrin-bound iron
`Non-transferrin-bound iron (NTBI), a free-form iron,
`can be detected in plasma when the iron binding capacity
`of transferrin is saturated[39]. This form of iron is able to
`generate free radical via the Fenton-type reactions, leading
`to peroxidative damage to membrane lipid and protein[40].
`The rate of NTBI uptake into cells is approximately
`300-fold greater than that of transferrin-bound iron[41]
`due to its independence on the presence of transferrin
`receptor[42] and none of feedback-regulated process[43].
`Moreover, there is a positive correlation between the rate
`of NTBI uptake and cellular iron content[44]. Further-
`more, a recent study demonstrated a direct correlation
`between NTBI and vital organ damage in thalassemia
`patients[45]. In a normal individual, there is no detectable
`NTBI[46]; on the other hand, hemochromatosis patients
`exhibit higher NTBI levels than controls[47]. The growing
`evidence on NTBI suggests that it could be a good index
`of iron overload in TM patients.
`Despite these facts, currently there is neither a cut-
`point threshold to imply cardiac iron overload status nor
`even a universally accepted method for NTBI measure-
`ment at the present time[48]. Importantly, a poor correla-
`tion was found between the methods in a recent inter-
`laboratory survey[49]. As a consequence, these limitations
`minimize its use in clinical practice.
`
`Cardiac magnetic resonance T2*
`Cardiac magnetic resonance T2* (CMR T2*) has become
`a widely used tool for its accurate and non-invasive tech-
`nique to measure iron deposition in heart[50]. Currently,
`this technique has been proven to be the most sensitive
`index and reproducible to assess cardiac iron available
`today[50,51]. Anderson et al[16] first reported a significant
`relationship between myocardial T2* below 20 ms and
`cardiac function parameters, such as LVEF (r = 0.61, P
`< 0.0001), left ventricular (LV) end-systolic volume index
`(r = 0.50, P < 0.0001), and LV mass index (r = 0.40, P <
`0.001). A later study confirmed the correlation of myo-
`cardial T2* with not only systolic function but also dia-
`stolic function as well[52]. Moreover, an increase of myo-
`cardial T2* was also in accordance with improved cardiac
`function[17]. Previous studies in a fresh postmortem iron
`overloaded heart[53] and a gerbil model of iron overload[54]
`clearly demonstrated a negative correlation between
`CMR T2* values and myocardial iron deposition. It also
`confirmed the earlier studies that iron loading was depos-
`ited mostly in the epicardium and myocardium[35,55]. Until
`now, no clinical scenario other than cardiac iron overload
`is found to cause myocardial T2* below 20 ms[50]. Thus,
`these data implied that CMR T2* is more specific to car-
`diac iron status than other previously mentioned meth-
`ods.
`The prospective study by Kirk et al[56] indicated the
`significant strong association between cardiac T2* values
`and risk of heart failure development in TM patients. It
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`Koonrungsesomboon N et al. Detection of cardiac involvement in thalassemia
`
`Table 1 Summary of the controversial correlation between cardiac magnetic resonance T2* and serum ferritin in thalassemia major
`
`Population/size
`TM/652 patients
`
`TM/776 patients
`
`TM/167 patients
`
`TM/106 patients
`TM/60 patients
`TM/20 patients
`TM/47 patients
`
`TM/19 patients, SCD/17 patients Cross sectional
`
`Type of study
`Prospective
`
`Retrospective
`
`Prospective
`
`Findings
`Significant correlation between cardiac T2* and ferritin
`(r2 = 0.003, P = 0.04)
`Significant relationship between cardiac R2* and ferritin
`(r = -0.359, P < 0.0001)
`Myocardial T2* was correlated with serum ferritin
`(r = -0.34, P < 0.001)
`Cardiac 1/T2* was correlated with ferritin level
`(r2 = 0.33, P = 0.01)
`Prospective No significant correlation between heart T2* and serum ferritin
`Prospective
`Serum ferritin did not correlate with cardiac iron values
`Prospective
`No correlation between serum ferritin and cardiac T2*
`Retrospective
`Cardiac T2* was not associated with the serum ferritin
`
`Correlation
`/
`
`Ref.
`Kirk et al[56]
`
`/
`
`/
`
`/
`
`×
`×
`×
`×
`
`Marsella et al[59]
`
`Tanner et al[60]
`
`Wood et al[61]
`
`Anderson et al[16]
`Merchant et al[57]
`Kolnagou et al[58]
`Bayraktaroğlu et al[22]
`
`TM: Thalassemia major; SCD: Sickle cell disease.
`
`Table 2 Summary of the correlation between cardiac magnetic resonance T2* and cardiac function in thalassemia major
`
`Population/size
`TM/776 patients
`TM/106 patients
`
`TM/167 patients
`TM/67 patients
`
`TM/33 patients
`
`TM/47 patients
`
`TM/19 patients,
`SCD/17 patients
`
`Type of study
`Retrospective
`Prospective
`
`Findings
`Significant correlation between LVEF and cardiac R2* (r = -0.327, P < 0.0001)
`Significant correlation of myocardial T2* below 20 ms with LVEF (r = 0.61, P <
`0.0001), LVESVi (r = 0.50, P < 0.0001), and LV mass index (r = 0.40, P < 0.001)
`Significant relationship between myocardial iron and LVEF (r = 0.57, P < 0.001)
`Prospective
`Cross sectional Myocardial T2* related to LV diastolic function (EPFR, r = –0.20, P = 0.19; APFR,
`r = 0.49, P < 0.001; EPFR/APFR ratio, r = –0.62, P < 0.001)
`Cross sectional Good correlation of DT, Tei index and E/Em index with cardiac T2* values (P <
`0.05, r = 0.70-0.81) and weak correlation of E/A with T2* (P < 0.05, r = -0.44)
`Significant correlations of the myocardial T2* with LVESVi and LVEDVi (r =
`-0.32, P = 0.027; r = -0.29, P = 0.046, respectively)
`Significant relationship between LVEF and myocardial T2*
`
`Retrospective
`
`Cross sectional
`
`Correlation
`/
`/
`
`Ref.
`Marsella et al[59]
`Anderson et al[16]
`
`/
`/
`
`/
`
`/
`
`/
`
`Tanner et al[60]
`Westwood et al[52]
`
`Barzin et al[84]
`
`Bayraktaroğlu et al[22]
`
`Wood et al[61]
`
`TM: Thalassemia major; SCD: Sickle cell disease; LVEF: Left ventricular ejection fraction; LVESVi: Left ventricular end systolic volume index; LVEDVi: Left
`ventricular end diastolic volume index; EPFR: Early peak filling rate; APFR: Atrial peak filling rate; DT: Deceleration time; E/Em: Early diastolic peak in-
`flow velocity and early diastolic myocardial velocity ratio; E/A: Early and late transmittal peak flow velocity ratio.
`
`demonstrated that 98% of patients who developed heart
`failure had the cardiac T2* less than 10 ms, with a rela-
`tive risk (RR) of 160 (95%CI: 39-653). In the same study,
`the RR for cardiac T2* less than 6 ms was 270 (95%CI:
`64-1129). Moreover, T2* threshold of 10 ms for pre-
`dicted heart failure had a sensitivity of 97.5% (95%CI:
`91.3-99.7) and a specificity of 85.3% (95%CI: 83.3-87.2).
`This study also demonstrated the significant relation-
`ship between cardiac T2* values and a risk of cardiac
`arrhythmia development in TM patients, but weaker than
`a risk of heart failure. A cardiac T2* less than 20 ms was
`figured in 83% of patients who develop arrhythmia, with
`a RR of 4.60 (95%CI: 2.66-7.95). The RR for a cardiac
`T2* less than 6 ms was 8.79 (95%CI: 4.03-19.2). The
`T2* threshold of 20 ms for predicted cardiac arrhyth-
`mia had a sensitivity of 82.7% (95%CI: 73.7-89.6) and a
`specificity of 53.5% (95%CI: 50.8-56.2). In addition, this
`prospective study clearly demonstrated the link between
`myocardial T2* and cardiac events. The one year risk of
`heart failure development was shown to be 14%, 30%,
`and 50% for T2* between 8-10, 6-8 and less than 6 ms,
`respectively. Therefore, myocardial T2* less than 10 ms
`
`strongly indicated clinically significant cardiac iron over-
`load and an increase in risk of developing heart failure in
`TM patients.
`When compared with conventional iron monitoring
`parameters, the correlation between CMR T2* and serum
`ferritin in TM patients has not been concluded (Table 1).
`Several studies indicated that serum ferritin was not cor-
`related with cardiac T2*[16,22,57,58]. However, other studies
`with larger population size showed a weak relationship
`between serum ferritin and heart T2*[56,59-61]. Because se-
`rum ferritin is raised even in many common conditions
`such as inflammation or hepatic disease[14], the contro-
`versial correlation could be from subjects with a different
`underlying status included in each study. As a result, a
`guideline for intensive chelation therapy based on serum
`ferritin may be inappropriate for cardiological manage-
`ment in TM patients.
`A prospective study of Tanner et al[62], which recruited
`167 TM patients, showed the significant association be-
`tween heart T2* values and LVEF. Patients with mild,
`moderate and severe cardiac iron overload (T2* 12-20, 8-12
`and less than 8 ms, respectively) had impaired LVEF in
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`Koonrungsesomboon N et al. Detection of cardiac involvement in thalassemia
`
`Table 3 Comparison of various methods to evaluate cardiac iron overload in thalassemia patients
`
`Method
`Serum ferritin
`
`Echocardiogram
`
`Liver biopsy
`
`Myocardial biopsy
`
`ECG
`
`SQUID
`
`NTBI
`
`CMR T2*
`
`Advantages
`Easy and available
`Inexpensive
`
` Easy and available
` Inexpensive
` Total body iron estimation[32]
`
`Easy and available
`Inexpensive
` Standardized noninvasive index for liver iron[36]
`
` Direct parameter of freeform iron resulting in
`peroxidative damage[87]
`
`Method of choice for the assessment of tissue iron deposition in
`last decade[51]
` Noninvasive measurement of cardiac iron deposition[50]
` Available
` High sensitivity and reproducible[50]
` Correlation with clinical outcome[16,17,56,62,63]
`
`Disadvantages
`Poor predictor of iron overload[85,86]
`Nonspecific for cardiac iron
`Altered by many conditions[14]
`Late indicator of cardiac involvement[21,23]
`
`Invasive
`No correlation with myocardial iron deposition[33]
`Invasive
`No correlation with cardiac iron status and function[34]
`Ineffective screening parameter for cardiac iron overload[25,31]
`
`Lack of availability, technical demands, and reproducibility
`Costly
`Application for the study of heart iron pending
`Limited availability
`No generally accepted method[48], and poor correlation
`between methods[49]
`Costly
`
`ECG: Electrocardiogram; SQUID: Superconducting quantum interference device; NTBI: Non-transferrin-bound iron; CMR T2*: Cardiac magnetic resonance T2*.
`
`5%, 20% and 62%, respectively (P < 0.001). Table 2 sum-
`marized studies that showed the significant correlation
`between CMR T2* and cardiac function in TM patients.
`These studies suggest that myocardial T2* could be a
`useful application to determine cardiac iron overload
`tending to deteriorate cardiac function. As a result, CMR
`T2* may be suitable for use as an assessment of cardiac
`iron deposit in thalassemia patients for early detection
`of the cardiac iron status before the detection of clinical
`signs and symptoms of iron overload cardiomyopathy.
`Since several studies showed a remarkably strong corre-
`lation of heart T2* value with clinical cardiac complications,
`including heart failure and arrhythmia, CMR T2* had been
`applied to monitor cardiac iron deposition in TM patients
`in UK[63,64]. Interestingly, the mortality rate was significantly
`reduced. Nowadays, CMR T2* is recognized as the method
`of choice for evaluation of cardiac iron deposition in TM
`patients[51]. However, the limitation of this technique is
`its rather expensive cost and only limited medical centers
`around the world are equipped with this technique.
`The pros and cons of different approaches that
`monitor cardiac iron overload condition in thalassemia
`patients are summarized in Table 3.
`
`HRV IN THALASSEMIA MAJOR
`HRV is used to indicate the variation over time of the
`period between successive heartbeats and determine
`cardiac autonomic function and overall cardiac health[65].
`HRV analysis has been used to determine the cardiac au-
`tonomic function in patients with post-myocardial infarc-
`tion[66,67]. Reduced HRV parameters were associated with
`
`a significant increased mortality in these patients[68,69]. A
`prospective study indicated that HRV analysis on 1-year
`post-myocardial infarction follow-up patients also had
`prognostic significance[70]. Furthermore, HRV parameters
`have been shown to a strong predictor of mortality in
`patients with heart failure[71,72], cardiac transplantation[73],
`and diabetic neuropathy[74].
`Due to its non-invasiveness and easy derivation, HRV
`has been investigated as one of the promising parameters
`to initially detect cardiac involvement and has been wide-
`ly studied in thalassemia in the last decades. A number of
`studies on HRV in TM patients have been reported since
`Franzoni et al[75] first proposed that HRV was depressed
`in TM patients. A summary of previous studies that ex-
`hibited the significantly reduced HRV parameters in TM
`patients and thalassemic mice is described in Table 4. All
`of previous studies reported that HRV parameters were
`reduced both in TM patients and thalassemic mice, indi-
`cating that thalassemic condition exerted some degrees
`of cardiac autonomic dysfunction. A recent study which
`investigated autonomic function by six quantitative au-
`tonomic function tests demonstrated that the prevalence
`of subclinical autonomic function impairment was higher
`in thalassemia patients compared to controls[76]. This re-
`sult confirmed that thalassemia patients have autonomic
`dysfunction in some degree. In prospective studies by
`Kardelen et al[77] and De Chiara et al[78], no evidence of
`abnormal echocardiographic finding was shown in TM
`patients with reduced HRV. Therefore, a significantly
`reduced HRV could be an early indicator of preclinical
`stage of heart disease in TM group. Nevertheless, the evi-
`dence of HRV in TM patients has not been extensively
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`August 26, 2013|Volume 5|Issue 8|
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`

`Koonrungsesomboon N et al. Detection of cardiac involvement in thalassemia
`
`Table 4 Summary of heart rate variability findings from both clinical and basic studies in thalassemia
`
`Population/size
`34 TM patients and 20 healthy subjects
`
`32 TM patients and 46 control subjects
`19 TM patients and 19 healthy volunteers
`
`100 TM patients and 60 healthy controls
`
`48 Thalassemia patients and 45 healthy subjects
`
`9 TM patients and 9 healthy subjects
`
`21 TM patients and 15 healthy subjects
`
`13 wildtype, 13 HbE/β thalassemia and 13 muβ+/
`− mice
`810 wildtype and 810 heterozygous betaknockout
`mice
`12 wildtype and 12 heterozygous betaknockout
`mice
`
`Type of study
`Prospective
`
`Cross sectional
`
`Cross sectional
`
`Findings
`Significantly depressed both time and frequency domain
`HRV parameters in TM patients
`Significantly reduced all HRV parameters in TM patients
`Prospective
`Cross sectional Significantly lower both time and frequency domain HRV
`parameters in the TM group
`Lower SDNN in TM with ectopia while markedly
`increased LF/HF ratio in this group.
`Significantly reduced time domain parameters in the
`thalssemia group
`Cross sectional Significantly lower LF/HF ratio during tilt in TM patients
`than in control subjects
`Significantly lower in all HRV parameters in TM group
`than in control group
`Depressed all HRV parameters in the heterozygous
`βglobin knockout mice (muβ+/−)
`Prospective Higher LF ⁄ HF ratio in thalassemic mice than those in the
`wild type
`Depressed HRV in betathalassemic mice compared to
`wild type
`
`Cross sectional
`
`Cross sectional
`
`Prospective
`
`Ref.
`Rutjanaprom et al[20]
`
`Kardelen et al[77]
`Franzoni et al[75]
`
`Oztarhan et al[88]
`
`Gurses et al[89]
`
`Veglio et al[90]
`
`Ma et al[91]
`
`Incharoen et al[92]
`
`Kumfu et al[82]
`
`Thephinlap et al[93]
`
`TM: Thalassemia major; HRV: Heart rate variability; SDNN: Standard deviation of all NN intervals; LF: Low frequency power; HF: High frequency power.
`
`Table 5 Summary of the correlation between HRV and serum ferritin in thalassemia major
`
`Population/size
`34 TM patients and
`20 healthy subjects
`19 TM patients and
`19 healthy volunteers
`21 TM patients and
`15 healthy subjects
`
`Type of study
`Prospective
`
`Findings
`No correlations between HRV parameters and serum ferritin
`
`Correlation
`×
`
`Ref.
`Rutjanaprom et al[20]
`
`Cross sectional
`
`No correlation between HRV parameters and serum ferritin
`
`Cross sectional
`
`No relationship of HRV parameters with serum ferritin
`
`×
`
`×
`
`Franzoni et al[75]
`
`Ma et al[91]
`
`TM: Thalassemia major; HRV: Heart rate variability.
`
`Table 6 Summary of the relationship between heart rate variability and cardiac function in thalassemia major
`
`Population/size
`34 TM patients and
`20 healthy subjects
`32 TM patients and
`46 control subjects
`19 TM patients and
`19 healthy volunteers
`20 TM patients
`
`Type of study
`Prospective
`
`Findings
`None of the echocardiographic parameters was correlated with HRV
`
`Correlation
`×
`
`Ref.
`Rutjanaprom et al[20]
`
`Prospective
`
`Cross sectional
`
`Prospective
`
`Reduced HRV were described in TM despite no echocardiographic
`abnormality
`No correlation between HRV parameters and echocardiographic
`parameters
`Abnormal HRV in TM with no evidence of ventricular dysfunction
`
`×
`
`×
`
`×
`
`Kardelen et al[77]
`
`Franzoni et al[75]
`
`De Chiara et al[78]
`
`TM: Thalassemia major; HRV: Heart rate variability.
`
`investigated when compared to that in post-myocardial
`infarction patients. Until now, none of studies has fo-
`cused on the association between HRV and mortality in
`TM patients.
`After the first report of HRV in TM patients by Fran-
`zoni et al[75], several studies have examined HRV in TM
`patients in order to seek the correlation between HRV
`and currently used iron overload parameters. No cor-
`relation between HRV parameters and serum ferritin in
`TM patients has been demonstrated (Table 5). Moreover,
`
`no correlation between HRV parameters and cardiac
`function in TM patients has been shown (Table 6). It is
`possible that HRV is not correlated with iron overload
`condition because several anemic diseases other than
`thalassemia, including sickle cell anemia[79], iron deficiency
`anemia[80], vitamin B12 deficiency anemia[81], could also
`impair cardiac autonomic function. Nevertheless, some
`evidence demonstrated that autonomic status determined
`by HRV is correlated with iron overload condition. In
`a study with thalassemic mice[82], it has been shown that
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`275
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`Apotex Tech.
`Ex. 2028
`August 26, 2013|Volume 5|Issue 8|
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`

`

`Koonrungsesomboon N et al. Detection of cardiac involvement in thalassemia
`
`those thalassemic mice had a higher Lfnu, lower Hfnu,
`and higher Lf/Hf ratio than those in the wild-type mice.
`More interestingly, iron administration in both types of
`mice resulted in significantly higher NTBI levels concom-
`itant with increased Lfnu and Lf/Hf ratio and decreased
`Hfnu. Moreover, iron chelator significantly decreased the
`Lfnu, Lf/Hf ratio, and increased the Hfnu in those iron
`overload thalassemic mice. This prospective study sug-
`gested that iron overload condition could contribute to
`progressive deterioration of the impaired cardiac auto-
`nomic function.
`In conclusion, although CMR T2* is now recognized
`as the method of choice in evaluation of iron deposition
`in the heart[51], evidence suggested that TM patients must
`be prevented