Correlation between Myocardial Iron Overload Detected by CMRT2* and Left Ventricular Function Assessed by Tissue Doppler Imaging in Patients with Thalassemia Major.

Background: Iron overload and cardiac dysfunctions are common complications in patients with thalassemia major (TM). Different imaging methods can be used to detect ventricular dysfunction in these patients. In this study, we aim to understand the value of tissue Doppler imaging (TDI) in the detection of myocardial dysfunction in patients with TM who have been diagnosed with iron overload using cardiovascular magnetic resonance CMRT2*.
Methods: In this cross-sectional study, fifty patients with TM diagnosed with iron overload who had no clinical signs and symptoms of cardiac dysfunction were chosen as a case group. The control group included fifty sex- and age-matched healthy participants without a history of cardiac and hematological diseases. TDI, pulsed wave Doppler (PWD), and standard echocardiography were performed to study the left ventricular function, and cardiac iron overload assessed by CMRT2*. Then, the patients with TM were divided into two subgroups and compared with each other. Group 1a includes individuals with T2* value <20 ms and group 1b T2* value >20 ms.
Results: There was no significant difference between the standard echocardiography results and PWD parameters of the case and control groups; however, CMRT2* findings and TDI parameters were different between the case and control groups. CMRT2* findings also were not correlated with PWD parameters. In group 1a, CMRT2* findings were negatively correlated with age, E', A', early deceleration time, and isovolumetric relaxation time and positively correlated with E/E' ratio. Finally, PWD and TDI parameters were significantly different between the two subgroups.
Conclusion: TDI can detect ventricular systolic and diastolic dysfunctions in earlier stages among patients with iron overload. It seems that TDI could detect abnormalities more accurately, and it is better to consider subclinical cardiac dysfunction in patients with even CMRT2* value of more than 20 ms and reevaluate them in future. Copyright:

INTRODUCTION

Cardiomyopathy and arrhythmias are the main causes of death in patients with beta-thalassemia major (TM). A regular blood transfusion can cause iron overload in these patients, and due to this complication, they commonly experience left ventricular systolic dysfunction and congestive heart failure (CHF) in the third decade of life.[123] Noninvasive diagnostic imaging techniques are the best way to detect early iron accumulation in patients. CMRT2* is an effective method to measure iron overload in tissue and is used to estimate the amount of iron in the myocardium.[14]

CMRT2* cannot be used as a screening test for iron overload in patients with TM as it is not cost-effective and widely available at all health-care centers. Cardiologists usually order a CMRT2* test if echocardiographic findings are abnormal in a patient with TM.

Other imaging techniques have been usually proposed to detect cardiac dysfunctions and cardiomyopathies in these patients, and tissue Doppler imaging (TDI) is one of them. It is a technology based on echocardiography of the heart muscles to measure the velocities of the myocardium through detecting Doppler shift frequencies produced by the contraction and relaxation of longitudinal muscle fibers.[5]

The present study aimed to clarify the value of TDI in the detection of myocardial dysfunction in asymptomatic patients with TM who diagnosed with iron overload by CMRT2*.

METHODS

This cross-sectional study was performed on patients with TM, who had no cardiac symptoms of iron overload, admitted to the hospital to receive a blood transfusion from April 2018 to April 2019. The study protocol was approved by the local research ethics committee at the Arak University of Medical Sciences (IR.ARAKMU.REC.1397.346). Excluded criteria were (1) the presence of blood pressure >140/90, (2) arrhythmia, and (3) left ventricular ejection fraction (LVEF) <55%.

Finally, the case group included fifty patients with TM aged 8 to 37 years, who regularly underwent blood transfusion at 2–4 weeks intervals to have hemoglobin (Hb) levels of 10 g/dl or higher. Iron chelation therapy has been performed for all of them according to hematology guidelines. The control group included fifty sex- and age-matched healthy participants without a history of cardiac and hematological diseases who had a normal physical examination, ECG and echocardiography findings, Hb, and serum ferritin level.

Echocardiography

Echocardiography assessment was performed by a 3–8 MHz probe by ViVid 6 (GE Medical Systems, General Electric, USA) and from the parasternal long-axis and the apical four chambers in partial left decubitus position. Before cardiovascular assessments, all the participants rested for at least 30 min. In both groups, the ventricular functions were evaluated using M-mode, TDI, and pulsed wave Doppler (PWD). We utilized echocardiography parameters in five consecutive cardiac cycles to confirm the analysis according to the American Society of Echocardiography.

Standard echocardiography

Through transthoracic echocardiography, the following measurements were calculated: fractional shortening percentage, ejection fraction, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, the left atrium and aortic diameters ratio, the interventricular septal dimension in systole, left ventricular end-diastolic volumes, posterior wall thickness, and septum wall thickness apical four-chamber view.

Pulsed wave Doppler echocardiography

Doppler echocardiography recordings were obtained during normal respiration. Diastolic function was evaluated using PW Doppler, and mitral inflow velocities were measured in the apical four-chamber view. All the indexes of LV diastolic function, peak mitral inflow velocities at early (E) and late (A) diastole, E/A ratio, and early deceleration time (E-Dt) were examined during three consecutive cardiac cycles in both groups to be compared. To have accurate results, the sample volume was placed 2–3 mm above the mitral valve tip and the vector (transducer) was located parallel to the mitral valve from the apical window.

Tissue Doppler imaging echocardiography

Before performing Doppler tissue imaging (DTI) echocardiography, blood pressure was measured in all participants. Filters were also set to exclude high-frequency signals, and the Nyquist limit was adjusted to a velocity range of 15–20 cm/s to reduce measurement errors. Gains were minimized to allow for a clear tissue signal with minimal background noise.

The TDI parameters were assessed by placing the sample volume at the basal segment of the RV free wall for the tricuspid and the LV lateral wall for the mitral annulus. At the basal segment of the LV lateral wall, systolic myocardial velocity (S') was evaluated as a systolic parameter. Early (E') and late (A') diastolic velocities, (E'/A' ratio) and the isovolumetric relaxation time (IVRT) were also evaluated as diastolic parameters. The myocardial performance index (MPI) (IVRT + isovolumic contraction time [IVCT]/ET) was calculated to assess the left ventricular function. We calculated E/E' ratio, which is the index of LV filling pressure. At the basal segment of the RV free wall, S', E', A', E'/A' ratio, IVRT, IVCT, and MPI parameters were calculated to evaluate systolic and diastolic functions of the RV.

Measurement of serum levels of ferritin

Serum ferritin level was measured by an enzyme-linked immunosorbent (ELISA) (Awareness Technology, USA).

Cardiovascular magnetic resonance

CMRT2* was performed by Magneto Symphony Graniand 32, 1.5 Tesla (Siemens, Germany, 2003) and each MRI scan lasted 30–35 min for everyone. The scans were done by a radiologist technologist blinded to patients' medical conditions.

The respiratory triggering technique was applied for all participants, and a standard quadrature radiofrequency body soil was used for excitation and signal detection. A single short-axis mid-ventricular slice (10 mm) was acquired at 8 separate echo times. Each image was obtained during a 10–15-second breath-hold.

The different amounts of T2* were considered in two categories of normal (T2* >20 ms) and abnormal (T2* <20 ms). The case group was divided into subgroups according to CMRT2* results. Group 1a included individuals with T2 value <20 ms and group 1b consisted of those with T2 value >20 ms.

Statistical analysis

All variables were expressed as mean ± standard deviation. Data analysis was performed by IBM SPSS version 16 (Build 1.0.0.1347; IBM, New York, USA.), using independent samples Student's t-test and Chi-square test with a significant level of P < 0.05.

RESULTS

In this study, fifty patients with beta-TM (48% M, and 52% F), as a case group, were compared with fifty healthy participants (56% M, and 44% F) as a control group. Table 1 shows the demographic characteristics. There was no significant difference between the two groups in terms of body mass index, heart rate, systolic blood pressure, and diastolic blood pressure. The results of standard transthoracic echocardiography, PW Doppler, and TDI echocardiography are summarized in Table 2. There was no significant difference between the standard echocardiography results of the two groups. Moreover, CMRT2* findings were not correlated with PWD parameters. In group 1a, CMRT2* findings were negatively correlated with age, E', A', E-Dt, and IVRT and positively correlated with E/E' ratio. There was no correlation between CMRT2* findings and PWD parameters. Except for age, other demographic and clinical characteristics were not significantly different between the two groups of 1a and 1b [Table 3]. Table 4 shows a comparison of the PWD and TDI parameters in the case group, group 1a, and group 1b with healthy ones (the control group). Table 5 shows a comparison of the PWD and TDI parameters in groups 1a and 1b, which were significantly different.

Table 1

Demographic and clinical characteristics between thalassemia group and healthy group

Variables	Patient (n=50)	Control (n=50)	P
Gender (female/male)	26/24	28/22	0.688
Age (years)	23.58±7.94	24.77±6.34	0.410
BMI (kg/m2)	18.94±5.72	20.78±2.42	0.040
HR (bpm)	71.46±5.98	73.79±6.71	0.070
SBP (mmHg)	113.25±10.52	114.69±4.62	0.379
DBP (mmHg)	74.72±3.68	75.95±4.61	0.144
Hemoglobin	9.21±1.73	13.75±2.29	0.0001
Ferritin (ng/mL)	2391.65±409.72	110.93±55.97	0.0001
CMRT2*	23.37±5.71	-	-
Age of chelator therapy (years)	11.52±8.32	-	-
Age of blood transfusion (years)	13.73±7.29	-	-

BMI=Body mass index, HR=Heart rate, SBP=Systolic blood pressure, DBP=Diastolic blood pressure, CMRT2*= Cardiovascular Magnetic Resonance T2*

Table 2

Comparison of the standard echocardiography data between thalassemia group and healthy group

	Patient (n=50)	Control (n=50)	P
EF (%)	67.85±2.63	68.97±3.55	0.076
FS (%)	33.45±2.16	33.48±3.68	0.961
IVSD (mm)	3.73±1.59	3.56±1.90	0.629
LVPWD (mm)	3.12±1.59	3.10±1.46	0.948
IVSS (mm)	5.43±1.48	5.35±1.94	0.817
LVPWS (mm)	5.33±1.88	5.13±1.48	0.556
LVEDD (mm)	49.31±6.43	48.31±5.98	0.423
LVESD (mm)	34.87±7.89	32.93±7.67	0.216
AO/LA (ratio)	1.29±0.27	1.22±0.17	0.124

IVSD=Interventricular septal dimension in diastole, LVPWD=Left ventricular posterior wall dimension in diastole, IVSS=Interventricular septal dimension in systole, LVPWS=Left ventricular posterior wall dimension in systole, LVEDD=Left ventricular end-diastolic dimension, LVESD=Left ventricular end-systolic dimension, EF=Ejection fraction, FS=Fraction shortening, AO=Aorta diameter, LA=Left atrium diameter

Table 3

Demographic and clinical characteristics in two subgroups of thalassemia

	CMRT2* <20 (n=22)	CMRT2* >20 (n=28)	P
Gender (female/male)	10/12	16/12	0.412
Age	26.64±7.16	21.57±7.75	0.022
High	164.39±7.80	160.43±11.68	0.186
Weigh	58.41±11.5	51.64±13.17	0.590
BMI	21.55±3.33	19.75±3.36	0.066
Hemoglobin	9.32±1.12	9.45±0.72	0.635
Ferritin	1146.82±730.93	982.14±650.50	0.406

BMI=Body mass index, CMRT2*= Cardiovascular Magnetic Resonance T2*

Table 4

Comparison of the pulsed wave Doppler and tissue Doppler imaging in two subgroups of thalassemia

	Total (n=50), P	CMRT2* >20 (n=28), P	CMRT2* <20 (n=22), P	Control (n=50)
E (m/s)	102.20±8.01, 0.487	100.82±3.24, 0.045	101.10±7.68, 0.248	103.22±6.53
A (m/s)	54.87±5.82, 0.080	55.16±6.14, 0.131	54.36±5.32, 0.303	52.88±5.42
E/A (ratio)	1.88±0.23, 0.0001	1.69±0.26, 0.357	1.87±0.17, 0.0001	1.63±0.19
E-Dt (m/s)	135.86±22.70, 0.001	101.13±8.64, 0.0001	109.32±10.16, 0.0001	149.76±18.95
E’ (m/s)	18.21±2.60, 0.004	20.10±2.38, 0.912	16.73±1.63, 0.0001	20.02±3.40
A’ (m/s)	6.38±1.08, 0.036	6.94±1.20, 0.008	6.30±0.91, 0.0001	7.89±1.35
E’/A’ (ratio)	3.81±0.44, 0.004	2.95±0.45, 0.012	2.70±0.40, 0.0001	3.38±0.93
S’ (m/s)	8.49±1.20, 0.036	8.02±1.16, 0.008	7.53±1.39, 0.0001	9.09±1.60
LVMPI	0.41±0.09, 0.021	0.40±0.02, 0.016	0.43±0.05, 0.0001	0.37±0.08
E/E’ (ratio)	5.73±0.95, 0.002	5.69±0.68, 0.005	6.26±0.77, 0.0001	5.24±0.55
IVCT (m/s)	33.78±13.62, 0. 234	31.62±11.74, 0.733	38.99±10.66, 0.009	30.33±15.12
IVRT (m/s)	96.49±11.28, 0.008	93.01±5.27, 0.167	89.47±4.97, 0.786	90.04±12.53
ET (m/s)	251.24±43.36, 0.178	252.33±38.24, 0.371	251.25±41.36, 0.347	260.67±23.17

A=Peak velocity blood flow in late diastole, E=Peak velocity blood flow in early diastole, E-Dt=E-deceleration time, E’=Peak E myocardial velocity in early diastole, A’=Peak A myocardial velocity in late diastole, E’/A’=E/A myocardial velocity ratio, E/E’ ratio=Peak velocity blood flow in early diastole/peak E myocardial velocity in early diastole, S’=Systolic myocardial velocity, LVMPI=Left ventricular myocardial performance index, IVCT=Isovolumic contraction time, IVRT=Isovolumic relaxation time, ET=Ejection time, CMRT2*= Cardiovascular Magnetic Resonance T2*

Table 5

Comparison of the pulsed wave Doppler and tissue Doppler imaging in two subgroups of thalassemia

	CMRT2* >20 (n=28)	CMRT2* <20 (n=22)	P
E (m/s)	100.82±3.24	101.10±7.68	0.863
A (m/s)	55.16±6.14	54.36±5.32	0.40
E/A (ratio)	1.69±0.26	1.87±0.17	0.472
E-Dt (m/s)	101.13±8.64	109.32±10.16	0.004
E’ (m/s)	20.10±2.38	18.73±1.63	0.020
A’ (m/s)	6.94±1.20	6.30±0.91	0.037
E’/A’ (ratio)	2.95±0.45	2.70±0.40	0.043
IVRT (m/s)	93.01±5.27	89.47±4.97	0.019
S’ (m/s)	8.02±1.16	7.53±1.39	0.190
LVMPI	0.40±0.02	0.43±0.05	0.006
E/E’ (ratio)	5.69±0.68	6.26±0.77	0.009
IVCT (m/s)	31.62±11.74	38.99±10.66	0.025

A=Peak velocity blood flow in late diastole, E=Peak velocity blood flow in early diastole, E-Dt=E-deceleration time, E’=Peak E myocardial velocity in early diastole, A’=Peak A myocardial velocity in late diastole, E’/A’ratio=E/A myocardial velocity ratio, E/E’ ratio=Peak velocity blood flow in early diastole/peak E myocardial velocity in early diastole, S’=Systolic myocardial velocity, LVMPI=Left ventricular myocardial performance index, IVCT=Isovolumic contraction time, IVRT=Isovolumic relaxation time, ET=Ejection time, CMRT2*= Cardiovascular Magnetic Resonance T2*

DISCUSSION

The iron deposition in cardiac tissue would cause degeneration, fibrosis, and ventricular dysfunction. Even though serum ferritin levels measurement can indirectly evaluate the iron storage in the body, it might be elevated in other conditions such as inflammation, infection, and alcohol abuse, which is not valuable. The ferritin test would be useful if the levels can be measured in a long-term evaluation as the chronic levels of ferritin can predict cardiac mortality rate in patients with TM. Using cardiac CMRT2*, the iron overload in the myocardium can be measured. Myocardial siderosis could result in ventricular dysfunction and heart failure in patients with TM.

Various methods have been proposed for cardiac evaluation. Standard echocardiography is useful to study anatomical changes of the heart. PWD and TDI echocardiography are two methods for the evaluation of subclinical systolic and diastolic dysfunctions in patients. The present study was conducted to determine the association between cardiac CMRT2* findings and advanced echocardiographic LV function parameters in patients with TM. We evaluated the relationship between cardiac iron overloading by CMRT2* and left ventricular function assessed by conventional PWD and TDI. It was found that CMRT2* findings correlated with the TDI parameters.

Based on the results, PWD parameters indicated abnormalities in patients with CMRT2* values of <20 ms. What is important is that TDI parameters not only showed abnormalities in patients with CMRT2* values of <20 ms but also showed abnormalities in patients with CMRT2* values of more than 20 ms. It seems that TDI could detect abnormalities more accurately and maybe it is better to consider subclinical cardiac dysfunction in patients with even CMRT2* value of more than 20 ms. Then in future, it may be better to reevaluate patients with CMRT2* <20 ms after a while.

There are certain studies that have been performed on patients with TM with iron overload, their cardiac parameters in different imaging methods, and ventricular function. In a study by Alpendurada et al., it was found that myocardial iron deposition was related to right ventricular dysfunction and also predictive of left ventricular dysfunction.[6]

Iarussi et al. used pulsed DTI to examine myocardial functions in young patients with TM and compare the DTI parameters with standard Doppler echocardiography. They found similar TDI parameters between the patients and the control group. Besides, the TDI parameters and the filling patterns of standard Doppler left ventricular in the patients with normal left ventricular systolic function were similar to those with increased preload. Therefore, they concluded LV filling abnormalities can be absent in young patients without CHF and suggested that the development of heart failure is not mainly because of iron overload in young patients with normal LV function.[7]

A meta-analysis by Javier et al. showed that increased iron overload was related to left ventricular dysfunction, increased Tei index (MPI), and shortened deceleration time.[8] A study by Saravi et al. showed that PWD predicts myocardial iron overload and could be a useful method for screening suspected patients.[9] Besides, Vogel et al. reported that wall motion disorders were the primary signs of heart disease in patients with myocardial iron deposition even if they had a normal cardiac function. These wall motion disorders can be easily found by PWD.[10] Seldrum et al. showed that iron myocardial overload correlated with left ventricular systolic and diastolic dysfunctions. They also showed that the left ventricle had early involvement with the highest impact on T2*MRI and recommended the use of MRI for monitoring of the left ventricular systolic function in patients with iron overload.[11]

In a study by Leonardi et al., CMRT2* was a helpful predictive of heart failure in patients with TM since the CMRT2* findings were significantly associated with EF in the patients.[12] While patients with cardiac siderosis (T2* value <20 ms) were older and experienced more blood transfusion in our study, little data are available about the onset age of cardiac iron overload in patients with TM.[13] Most patients with hemoglobinopathy who received a blood transfusion and chelation therapy were older than 10 years when their CMRT2* was <20 ms.[14] Among patients with TM, there has been reported a few cases with myocardial iron overload at the age under 10 years, particularly in those with limited access to chelation therapy.[15] Younger patients with TM did not present different left or right ventricular function values compared to normal people despite an increase in left ventricular volumes and mass.[16]

In patients with a reduced ventricular function, a CMRT2* value <20 ms is correlated with iron overload. Furthermore, patients with T2* values <10 ms are at higher risk for heart failure.[14] In this study, no differences were detected between the two groups in terms of LV systolic dysfunction. As a result of increased preload and high cardiac output in anemia, an increase in LVEF, E, and A velocities in PWD, fractional shortening, and LV dimensions was detected in the case group.

Tissue Doppler parameters can detect regional systolic and diastolic myocardial dysfunction in early stages in patients with TM. In another study, myocardial velocities in the basal segments of the LV and interventricular septum were examined to evaluate the function of the walls. The results showed that longitudinal velocities progressively decrease from base to apex in healthy individuals.[5]

In a case–control study by Agha et al., on patients with TM, it was shown that patients without clinical cardiac dysfunction had abnormal left ventricular diastolic function with higher atrial diastolic left ventricular velocity (tricuspid annular A') and low tricuspid annular E'/A' ratio compared to controls. In the present study, patients with iron overload had no impairment of diastolic LV functions was evident despite having LV diastolic dysfunction.[16]

Based on another study, E'/A' <1 in TDI could more accurately show the diastolic dysfunction compared with E/A <1.[17] Using TDI, a decrease in S' velocities of both ventricles has been seen in patients with TM. Moreover, iron overload affects systolic function earlier than diastolic function in these patients.[18] In another study, the Tei index of LV was significantly higher in patients with TM. It was suggested that the Tei index, which is measured by TDI, can predict cardiac dysfunction in patients with TM.[19] In a study by Eghbali et al., CMRT2* findings were not correlated with serum ferritin levels in patients with TM; however, the findings were associated with serum Troponin T and echocardiography findings.[20]

Based on our result, TDI parameters were correlated with CMRT2* values, and it is possible that many young patients with TM have a subclinical cardiac dysfunction due to iron overload, which is detectable with TDI.

This study has some limitations, including a small sample size and the absence of long-term follow-up. A large random sample was required to distinguish the correlation between echocardiography parameters and CMRT2* levels. Also, we did not select the patients randomly to assess the intra and inter-observer variability. Also, the intra and inter-observer variability of the PWD and TDI measurements of the right ventricle were not calculated.

CONCLUSION

TDI can detect ventricular systolic and diastolic dysfunctions in earlier stages among patients with iron overload. It seems that TDI could detect abnormalities more accurately, and it is better to consider subclinical cardiac dysfunction in patients with even CMRT2* value of more than 20 ms and reevaluate them in future.

Ethical clearance

The study protocol was approved by the local research ethics committee at the University of Medical Sciences, (IR.ARAKMU.REC. 1397.346).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.