Strain Imaging by Speckle Tracking for the Assessment of Diastolic Dysfunction in Beta-Thalassemia Major Patients

Objectives: Strain imaging is a novel promising echocardiographic technique and strain imaging by speckle tracking has been reported recently in a few studies as a promising tool to detect early changes of myocardial deformation that could be related to myocardial iron over load in patients with β-thalassemia major. In this study, we investigated strain images in comparison with the cardiac T2* magnetic resonance imaging results. Materials and Methods: A total of 45 patients from a single institution’s pediatric and adult hematology centers were evaluated with strain echocardiography and T2* magnetic resonance imaging at concomitant out-patient visits. We grouped patients according to cardiac T2* magnetic resonance imaging results: <20 ms (Group 1, cardiac iron loading present) (n=12) and ≥20 ms (Group 2, no clinically significant cardiac iron loading) (n=33). Results: The median global longitudinal strain was measured as -19.9% (range -27.1% to -12%) in Group 1 and -20.7% (range -26.5% to -12.8%) in Group 2 (p=0.37). Using receiver operator curve analysis, global longitudinal strain value at a cutoff point of -20.45% in the ruling out T2*<20 ms with a sensitivity of 83% and a specificity of 54% was obtained. Conclusion: In conclusion, although T2* magnetic resonance imaging is the gold standard method, strain imaging echocardiography can be used for predicting cardiac iron accumulation, after validations were obtained in larger sample sizes.


acta medica ORIGINAL ARTICLE
A B S T R A C T Objectives: Strain imaging is a novel promising echocardiographic technique and strain imaging by speckle tracking has been reported recently in a few studies as a promising tool to detect early changes of myocardial deformation that could be related to myocardial iron over load in patients with β-thalassemia major. In this study, we investigated strain images in comparison with the cardiac T2* magnetic resonance imaging results.
Materials and Methods: A total of 45 patients from a single institution's pediatric and adult hematology centers were evaluated with strain echocardiography and T2* magnetic resonance imaging at concomitant out-patient visits. We grouped patients according to cardiac T2* magnetic resonance imaging results: <20 ms (Group 1, cardiac iron loading present) (n=12) and ≥20 ms (Group 2, no clinically significant cardiac iron loading) (n=33).
Results: The median global longitudinal strain was measured as -19.9% (range -27.1% to -12%) in Group 1 and -20.7% (range -26.5% to -12.8%) in Group 2 (p=0.37). Using receiver operator curve analysis, global longitudinal strain value at a cutoff point of -20.45% in the ruling out T2*<20 ms with a sensitivity of 83% and a specificity of 54% was obtained.
Conclusion: In conclusion, although T2* magnetic resonance imaging is the gold standard method, strain imaging echocardiography can be used for predicting cardiac iron accumulation, after validations were obtained in larger sample sizes.

Strain Imaging by Speckle Tracking for the Assessment of Diastolic Dysfunction in Beta-Thalassemia Major Patients INTRODUCTION
Cardiac iron accumulation is the most important cause of mortality for β-thalassemia major (BTM) patients [1]. Increased iron absorption due to ineffective erythropoiesis and chronic blood transfusions are the cause of iron accumulation for these patients [2] . Liver, heart and endocrine organs are the major sites of iron accumulation [2,3].
Cardiac T2* magnetic resonance imaging (MRI) is the gold standard, non-invasive and validated method for assessment and follow-up of myocardial iron overload indirectly [4]. Cardiac T2* value below 10 ms, is indicative for severe iron accumulation and T2* values above 20 ms indicates the absence of clinically significant iron accumulation. On the other hand, range of T2* value between 10-20 ms indicates cardiac iron loading [5,6]. However, access to cardiac T2* MRI is still limited in many centers [7].
Conventional echocardiography is suggested to be performed annually for BTM patients when they reach the age of ten. However, conventional echocardiography can only detect systolic dysfunction when iron overload reaches its severe levels in the late period of disease [8,9]. Strain imaging, also known as deformation imaging, is a novel promising echocardiographic technique which allows assessment of regional myocardial function [10]. Strain imaging can be done by using tissue doppler imaging or speckle tracking [11]. Speckle tracking is a recent echocardiographic approach which is a post-processing computer algorithm [10]. Strain imaging by speckle tracking was reported as a promising tool to detect early changes of myocardial deformation that could be related to myocardial iron over load in patients with BTM [12].
In this study, we aimed to compare strain echocardiography parameters and cardiac T2* MRI results of BTM patients form a single center.

Patient Population
A total of 45 patients from a single institution of pediatric and adult hematology centers with BTM diagnosis were evaluated with strain echocardiography and T2* MRI at concomitant outpatient visits. The echocardiographic evaluations and T2*MRI measurements were performed with Local Ethical Committee approval (GO-19386 Number) and informed consent were obtained from all patients/parents (for under 18 years old patients). Only the BTM patients who were on regular transfusion programme were included in this study. Patients with arrhythmias, hypertension, moderate to severe valvular diseases and congenital heart diseases were excluded. Mean serum ferritin levels of the last 12 months before assessment was also recorded.
Myocardial iron load was assessed using 1.5 Tesla scanner (Siemens Aera, Erlangen, Germany) for all patients. "Multi Echo Black Blood Gadolinium Related Enhancement (GRE)" images were obtained during the mid-diastolic phase of cardiac cycle to calculate T2*. Myocardial T2* were measured from mid-ventricular septum on short axis view. All cardiac T2* MRI assessments were evaluated by the same radiologist. Patients were grouped according to cardiac T2* MRI measurements: <20 ms (Group 1) and ≥20 ms (Group 2).

Echocardiographic Evaluation
Conventional transthoracic echocardiography was performed using GE Vivid E9 3D Echo by the same cardiologist who was blinded to the clinical data. Two-dimensional image examination and chamber quantification were performed in parasternal long-and short-axis views and apical four-, twochamber and long axis views, according to the recommendations of the European Association of Cardiovascular Imaging (EACVI) [13].

Statistical Analyses
Independent sample t test and Mann Whitney U tests were used for normally and non-normally distributed variables, respectively. Variables were described by using mean ± standard deviation (SD) for normally distributed variables and the median (minimum-maximum) value for non-normally distributed variables. The receiver operating characteristic (ROC) curve was used to obtain the optimal cut-off for global longitudinal strain value in diagnosing cardiac involvement by considering T2* MRI result as a gold standard test. Statistical significance level was considered as p<0.05. The data were analyzed with IBM SPSS Statistics for Win ver. 23 (IBM Corporation, Armonk, NY, USA).

RESULTS
The baseline patient's characteristics are presented in Table 1. Median age of patient population was 31.6 (minimum-maximum: 21.5 -47.1). The iron chelators that the patients were on during evaluation were summarized in Table 1. 66.6% and 66.7% of Group 1 and 2 patients were on deferasirox as iron chelation therapy, respectively.

Echocardiography and Doppler Findings
Left ventricle ejection fraction was measured as 60.58% and 64.26% in Group 1 and 2, respectively (p=0.01).

DISCUSSION
Diastolic dysfunction usually develops before systolic dysfunction in patients with BTM.
Myocardial iron accumulation makes early diastolic dysfunction without affecting the relaxation of the left ventricle. In the later period, systolic dysfunction develops as dilated cardiomyopathy. With the early detection of diastolic dysfunction, changes can be made with iron chelation therapy, and expected systolic dysfunction can be prevented [14]. In our study, left ventricle diastolic functions were evaluated with transmitral doppler and tissue doppler values. To our knowledge, E/e' ratio is an important predictor for increasing the left ventricle diastolic pressure. In our series, E/ septal e' ratio was significantly higher in group 1 and this finding showed that diastolic dysfunction was more prominent in group 1 consistent with Cardiac MRI findings.
Cardiac T2 * MRI is the gold standard tool for the assessment of myocardial iron deposition in BTM patients. However, T2* MRI is not available in every center which follows BTM patients. Other disadvantages of MRI are its contraindication in the presence of cardiac pacemaker and claustrophobia. Echocardiographic and strain assessment may be an alternative diagnostic tools to T2* MRI [15]. In the previous study conducted by Garceau P et al., showed that the ejection fractions were found as 59% and 64% in low T2* (high cardiac iron load) and normal T2* (normal cardiac iron load) groups, respectively. They also found no difference in two groups in terms of strain parameters except for E/A ratio [15]. In another study, peak atrial 2D strain was found as an early index of left ventricular diastolic dysfunction in BTM patients [16]. Atrial strain values were examined in this study with the 2D strain and there was no significant difference in longitudinal strain among the groups [16]. In our study, ventricular global longitudinal strain values were evaluated. Although the specificity was low, we found the cut-off value of global longitudinal strain as -20.45% to predict high iron overload (low T2* MRI) and this was different from other studies (-17% and -18.5%) [15,17].
In a recent study, global longitudinal strain was found as an early predictor for diastolic dysfunction in 122 thalassemia major and intermedia patients [17]. Pizzino et al. also showed that GLS -19.5% can be predictive for myocardial iron overload [18].
Our study was compatible with the results of these studies. However, in our study, the cut-off value of global longitudinal strain was found to be lower, interestingly.
It is important to realize the limitations of this study. First of all, our study population was small due to rarity of the BTM. However, we conducted 45 patients and this was enough to get significant biostatistical analysis. Secondly, measurement of iron burden was made only in the mid ventricular septum. Speckle tracking imaging is a segmental technique with a global value and physicians can compare global longitudinal strain in the mid ventricular septum. Finally, in the future, next studies may compare the treatment efficacy with speckle tracking and strain parameters.
In conclusion, although T2* MRI is the gold standard method to determine the cardiac iron load, strain imaging echocardiography can be used for predicting cardiac iron accumulation in thalassemia patients at T2*MRI absent centers. The patients who have impaired global longitudinal strain value (>-20.45%) might be suggested for evaluation with T2*MRI. Strain imaging by speckle tracking and left ventricular diastolic function parameters might be used as a screening tools in such centers that do not have T2*MRI.