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ORIGINAL ARTICLE Table of Contents  
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Longitudinal strain in beta thalassemia major and its relation to the extent of myocardial iron overload in cardiovascular magnetic resonance


1 Atherosclerosis Prevention Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2 Radiology Department, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
3 Sheikh Hospital, Pediatric Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
4 Clinical Research Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
5 Rajaie Cardiovascular Medical and Research Center, Tehran, Iran

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  Abstract 


Background: Iron overload is a common problem in beta-thalassemia major. Finding a reliable and available modality to determine the presence of iron overload in the initial stages might decrease the risk of cardiomyopathy. We sought a reliable echocardiographic index to assess the extent of iron overload. Methods: This cross-sectional study was conducted on patients with beta-thalassemia major from June 2016 to May 2017. All the patients underwent T2* magnetic resonance imaging, conventional echocardiography, tissue Doppler study, and strain imaging for the measurement of ventricular systolic function indices including the left ventricular global longitudinal strain (LVGLS). The echocardiographic findings were compared between those with myocardial iron overload (T2* ≤20 ms) and those without it (T2* >20 ms) and in the second phase between those with nonsevere overload (20 ms >T2* >10 ms) and those with severe overload (T2* ≤10 ms). Results: Forty-four patients, comprising 23 (52.35%) males and 21 (47.7%) females, were enrolled. All the patients were receiving chelating drugs. The LVGLS showed a significant difference between those with myocardial iron overload and those without it (P = 0.012). Accordingly, a cutoff value of −17.5 for the LVGLS had 100% specificity and 43.8% sensitivity. Concerning the distinction between nonsevere and severe iron overload states, the average LVGLS (P < 0.001), LV end-diastolic volume index (P = 0.016), and LV end-systolic index (P = 0.016) showed significant differences between the groups. Conclusions: The LVGLS might be used as a reliable echocardiographic index for defining myocardial iron overload.

Keywords: Beta-thalassemia major, echocardiography, iron overload, left ventricle, magnetic resonance imaging, myocardium


How to cite this URL:
Poorzand H, Manzari TS, Vakilian F, Layegh P, Badiee Z, Norouzi F, Morovatdar N, Sani ZA. Longitudinal strain in beta thalassemia major and its relation to the extent of myocardial iron overload in cardiovascular magnetic resonance. Arch Cardiovasc Imaging [Epub ahead of print] [cited 2018 Dec 14]. Available from: http://www.cardiovascimaging.com/preprintarticle.asp?id=238934



  Introduction Top


Beta-thalassemia major is a genetic disease caused by a defective gene that is responsible for beta-hemoglobin synthesis chains. Severe anemia secondary to the impaired synthesis of hemoglobin leads to lifelong dependence on blood transfusion.[1] This iron overload may result in the degeneration of cardiac fibers,[2] iron-induced cardiomyopathy,[3] progressive diastolic and systolic ventricular dysfunction, arterial stiffness, and early atherosclerosis.[4],[5] Furthermore, factors other than iron overloads such as the overexpression of adhesion molecules and cytokines have a role in cardiovascular problems in beta-thalassemia major.[6],[7]

Cardiac involvement and, thus, heart failure are the major cause of death in beta-thalassemia major.[8] Chelation therapy can postpone cardiac abnormalities by reducing myocardial iron overload and, therefore, diminish the risk of early mortality.[9] Despite iron-chelation therapy, congestive heart failure, arrhythmias, and cardiac death are still common in these patients.[10] Hence, an early diagnosis of myocardial dysfunction and refining iron-chelation therapy can prevent or stop iron cardiomyopathy.[11]

A number of diagnostic tests have been proposed for detecting cardiac iron overload;[12] they include myocardial biopsy, echocardiography, and cardiac magnetic resonance (CMR) imaging.[13],[14] Invasive endocardial biopsy should be repeated for several times in some cases due to the patchy involvement of iron overload. Cardiac T2* magnetic resonance imaging (MRI) is deemed the gold standard method for iron overload identification.[15],[16] T2* MRI has higher sensitivity, relatively shorter acquisition times, and better tissue iron quantification than T2.[17] However, this method is expensive, not widely available in all centers,[18] and not available for all patients due to the application of pacemakers, defibrillators, or severe claustrophobia.[12] There is a tendency toward the use of feasible and available methods capable of diagnosing myocardial overload. Given the dearth of data in the existing literature on the value of echocardiographic parameters, we conducted the present study on patients with beta-thalassemia major to find an echocardiographic parameter for the early detection of myocardial iron overload and its severity.


  Methods Top


Study design

The current cross-sectional study, conducted from June 2016 to May 2017, enrolled 44 patients with beta-thalassemia major who were admitted to Sarvar Pediatric Center at Dr. Sheikh Hospital, Mashhad, Iran. The demographic features and past medical history of the patients were gathered through predesigned questionnaires and interviews. The patients with a history of cardiovascular disease or risk factors for atherosclerosis (i.e., hypertension, dyslipidemia, smoking, and diabetes) were excluded. All the patients included were receiving treatment with an intravenous iron-chelating agent (Desferal) and had undergone blood transfusion 1 week earlier. Within 1 week after patient recruitment, heart T2* CMR followed by echocardiography was performed for the study population. The echocardiographer was blinded to the CMR results. Personal variations in the CMR interpretation and echocardiography analysis being one of the limiting biases, efforts were made to overcome it by interobserver agreement, whereby the consistency between the observers was assessed by calculating the kappa value. Values greater than 0.7 were considered to meet the criteria for interobserver reliability. The MRI measurements were performed with a 1.5-T MRI scanner (SIEMENS Magnetom Avanto) and a torso surface coil. Myocardial T2* was measured from a single mid-ventricular short-axis slice using a cardiac-gated multiecho gradient-echo sequence obtained in a single breath-hold. The T2* values were calculated using CMR software in the region of the ventricular septum [Figure 1]. The patients were classified to those with myocardial iron overload (T2* ≤20 ms) and those without it (T2* >20 ms). The extent of iron overload was then defined as nonsevere (10 ms <T2* ≤20 ms) and severe (T2* ≤10 ms).
Figure 1: Myocardial T2* plot, showing a non-rapid decline in signal intensity at longer echo times, compatible with the absence of iron overload

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All the echocardiographies were done using a Phillips IE33 scanner (Philips Ultrasound, Bothell, WA, USA) with matrix probe X5S by an echocardiographer, blinded to the CMR results. Conventional echocardiography, tissue Doppler, and strain imaging (two-dimensional [2D] speckle-tracking) were performed. Ventricular size and thickness, atrial size and septal thickness, ventricular systolic function (left ventricular ejection fraction [LVEF], S' for the right ventricular systolic function, longitudinal strain in the base and mid segments of the right ventricular free wall, and left ventricular global longitudinal strain [LVGLS]) were measured. For the measurement of the LVGLS, three apical views of the LV (i.e., four- and two-chamber and long-axis) were recorded in grayscale at a minimum frame rate of 30. The peak longitudinal strain in 17 myocardial segments was derived automatically with automated cardiac motion quantification software. The average of the values in all the segments was expressed as the GLS. In addition, mitral inflow Doppler assay and tissue imaging of the mitral annulus were done. The results of the echocardiographic examinations were compared with the CMR findings as a standard method.

Written informed consent was obtained from the whole study population and the study protocol was approved by the Ethics Committee of Mashhad University of Medical Sciences.

Statistical analysis

The data were entered in SPSS, version 16 (SPSS Inc., IL, USA). Descriptive analyses were conducted by calculating means, standard deviations, absolute frequencies, and relative frequencies. The receiver operating characteristic curve was utilized to calculate specificity and sensitivity. The Chi-square, Pearson, and Spearman tests were applied to assess the relation between the demographic features and the past medical history on the one hand and the development of cardiomyopathy on the other. Furthermore, the Kolmogorov–Smirnov and Shapiro–Wilk tests were used to assess the normality of the data. P < 0.05 was considered abnormal. In the statistical analyses, a confidence interval (CI) of 95% was considered significant.


  Results Top


The study population was comprised of 23 (52.3%) male and 21 (47.7%) female patients at a mean age of 23.51 ± 6.2 years (maximum = 40 and minimum = 13). [Table 1] depicts the baseline characteristics of the two study groups of those with and without myocardial iron overload. The groups were not statistically significantly different in terms of age, the ferritin level, and the LVEF (P = 0.31, P = 0.45, and P = 0.18, respectively), and nor was there any significant difference concerning the LVEF and the ferritin level between the group with severe iron overload and the group with nonsevere iron overload (P = 0.054 and P = 0.27, correspondingly). [Table 2] demonstrates the echocardiography findings in the patients with and without iron overload. The only measured parameter which was lower significantly in the iron-overloaded group was the LVGLS (−18.23 ± 3.41 vs. −20.28 ± 1.67; P = 0.012). The relationship between the LVGLS in 2D speckle-tracking echocardiography and T2* was assumed to be statistically significant (P = 0.001 and r = −0.42).
Table 1: Baseline characteristics of the patients

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Table 2: Echocardiographic findings in the patients with and without iron overload

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Another analysis was done based on the severity of iron overload (nonsevere vs. severe), the results of which are presented in [Table 3]. Significant differences were found between the two groups in the average LVGLS (P < 0.001), the LV end-diastolic volume index (P = 0.016), and the LV end-systolic index (P = 0.016).
Table 3: Echocardiography findings in the patients with nonsevere or severe iron overload and their relation with T2*cardiac magnetic resonance imaging

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The area under the curve of the LVGLS for the diagnosis of myocardial iron overload was 0.69 (95% CI: 0.51 to 0.86 and P = 0.03) [Figure 2].
Figure 2: Receiver operating characteristic curve to calculate the specificity and sensitivity of global longitudinal strain in the definition of iron overload

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The specificity and sensitivity of the different values of the LVGLS were assessed to define myocardial iron overload. At a cutoff point of −17.5, the average LVGLS had a specificity of 100% and a sensitivity of 43.8%.


  Discussion Top


In our patients with beta-thalassemia major, the LVGLS was significantly lower in those with myocardial iron overload than in those without it. Previously proposed as an indicator of the LV systolic function,[19] the LVGLS can also be drawn upon to define the underlying myocardial dysfunction,[20] even in those without apparent cardiac abnormalities. Cheung et al.[21] found no significant differences regarding the GLS between their patients with beta-thalassemia and their healthy controls; however, they stated that the T2* MRI findings positively correlated with the longitudinal early diastolic strain rate. Cusmà Piccione et al.[22] aimed to detect the early stages of cardiac problems in patients with thalassemia by comparison with healthy controls and reported that the LV longitudinal deformation could be found in patients with even minor iron overload. Linear regression analysis in this study yielded a significant relation between longitudinal strain and myocardial T2* (r = 0.53 and P = 0.001). Several other studies have found significant impaired longitudinal and circumferential strain and early diastolic strain rates in the iron-overloaded myocardium.[12],[21] Aypar et al.[23] compared patients with iron overload (T2* ≤20 ms) and those without significant iron overload (T2* >20 ms) and found significant differences both in the regional peak myocardial early diastolic velocity (Em) of the basal septal wall and in the peak myocardial systolic velocity (Sm) of the mid-lateral LV wall. The authors reported that regional systolic and diastolic dysfunction in the septal and lateral walls correlated with the presence of iron overload. In contrast with the finding of their study, we found no significant differences in terms of Sm and Em between those with and without iron overload. It is also deserving of note that the global diastolic function is believed to remain intact until the last stages of the disease.[20]

Iron overload in patients with beta-thalassemia leads to myocardial toxicity and iron-mediated oxidative stress, which in turn causes damage to cell organelles including lysosomes, mitochondria, and sarcoplasmic membranes of myocytes. The process ends with cell apoptosis, leading to a range of insidious cardiomyopathies from subclinical alterations to obvious ventricular dilatation and dysfunction.[24],[25] Subendocardial fibers are the parts most susceptible to damage initiated, especially by hypoxemia, which is common in the case of beta-thalassemia anemia and is usually the cause of global longitudinal impairment.[26]

With respect to the determination of iron-overload severity, we found that the average LVGLS and the LV end-diastolic and end-systolic diameters were the significant indicators of the severity of myocardial iron overload. A study on pediatric patients suffering from beta-thalassemia major showed lower declaration times and higher E/Em ratios in the cases with severe iron overload.[27] Our study found no significant difference in the declaration time regarding the severity of iron overload, which may be due to our more accurate classification of iron overload severity using T2* MRI instead of the ferritin level, which was employed in the abovementioned study. Ferritin levels have been found to be unreliable for the detection of iron overload compared with T2* MRI, which is widely considered dependable.[16],[28],[29]

The salient limitation of our study is the 1-week gap between the T2* MRI and echocardiographic studies. Another point that can be mentioned as either an empowering or a limiting factor is the case selection from a specialized pediatric center, which may have caused selection bias. However, selecting cases from children populations can eliminate other cardiac abnormalities concomitant with aging.


  Conclusions Top


Echocardiography could be proposed for the assessment of myocardial iron overload and its severity in patients with beta-thalassemia major. The average LVGLS, when compared with T2* MRI as a reliable diagnostic test, showed sufficient reliability for use as an indicator of iron overload.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Correspondence Address:
Farveh Vakilian,
Associate professor of Cardiology, Fellowship in Heart failure. Atherosclerosis Prevention Research Center, Faculty of Medicine, Mashhad university of Medical Sciences, Mashhad
Iran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ACVI.ACVI_6_18



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    -  Manzari TS
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    -  Morovatdar N
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