Tissue Doppler echocardiography in patients with thalassaemia detects early myocardial dysfunction related to myocardial iron overload

M Vogela,*, L.J Andersonb, S Holdena, J.E Deanfielda, D.J Pennellb and J.M Walkera

a Departments of Cardiology and Grown-up Congenital Heart Disease, University College Hospitals, London, UK
b Cardiac Magnetic Resonance Unit, Royal Brompton Hospital, London, UK

Received May 13, 2002; accepted May 22, 2002 * Correspondence: Dr Michael Vogel, GUCH Department, 5th Floor Jules Thorn Building, The Middlesex Hospital, Mortimer Street, London W1N 8AA, UK

Abstract

Aims To compare an echocardiographic method for detecting abnormal cardiac function before development of overt cardiomyopathy with a recently validated technique of quantifying myocardial iron load.

Methods and results We examined thalassaemia patients whose myocardial iron load had been evaluated with magnetic resonance imaging (MRI). By tissue Doppler echocardiography, myocardial velocities were sampled continuously from base to apex in the RV and LV free wall, and the septum in 52 patients aged 29.2 (14.2–43.1) years and 52 age-matched controls. Ninety-six percent of patients had normal LV ejection fraction by MRI. Thirty-eight (73%) had abnormal iron loading of the myocardium, and 33 of those had regional wall motion abnormalities detected in the septum (n=29), LV (n=2), RV (n=1), and septum plus LV (n=1). The incidence of wall motion abnormalities was significantly higher (P<0.04) in patients with myocardial iron overload (87%) than in the 14 without (35%). Furthermore, myocardial iron overload was suggested by a low T2*(15.1±15.8 ms) in patients with wall motion abnormalities vs those with normal wall motion (T2*: 30±19 ms) (P<0.007).

Conclusions Wall motion abnormalities may represent an early sign of cardiac disease despite preserved global function. The regional abnormalities are related to iron overload and easily detectable with tissue Doppler echocardiography.

Key Words: Echocardiography • heart failure and thalassaemia • magnetic resonance imaging

Introduction

Life expectancy in patients with thalassaemiamajor is still limited by development of congestive heart failure due to a cardiomyopathy1 associated with iron over-load.2 Aggressive chelation therapy may prevent, delay or even reverse myocardial dysfunction, but once overt heart failure is present only 50% of patients survive. The goal therefore is to begin treatment while the cardiomyopathy is still reversible.3 However, early recognition ofpatients at risk of heart failure has been difficult, because global left ventricular function and exercise capacity in chronically transfused patients with iron overload may remain normal until late in the disease process.4,5 Quantifying myocardial iron content has only recently become possible using magnetic resonance imaging (MRI).6,7 However, MRI is not widely available, but is time consuming and expensive; this will limit the application of this technique especially in the developing countries where thalassaemia is most common. Echocardiography is more widely available. We therefore undertook this study to investigate whether tissue Doppler echocardiography (TDE) could be used to estimate functional consequences of MRI documented myocardial iron overload in patients with thalassaemia.8,9

Methods

Patient selection
Between January and October 2000 we examined 52 patients attending a specialist cardiac clinic for haemoglobinopathies. More than 30% of the UK thalassaemia population (a total of 700) attend this service. Patients who had undergone MRI myocardial iron assessment for clinical reasons, within the previous 30 days, were selected for examination by TDE. Forty-nine patients with thalassaemia major, and three with beta-thalassaemia intermedia were included. Patients with a history of heart failure were excluded. The majority (80%) of patients came from the Mediterranean region, and 20% from the Indian subcontinent. None of the patients had clinical signs of congestive heart failure at thetime of examination. Twelve (23%) patients had diabetes. Four (8%) patients took antiarrhythmic medication for atrial flutter (n=2) or fibrillation (n=2) documented by 24 h Holter monitoring. A further nine (17%) patients reported palpitations but had no documented arrhythmias and were not on specific therapy. Long-term chelation therapy was by desferrioxamine in all patients. The average serum ferritin level for the previous year was 1700±1500 µg.1–1, with 42 (81%) patients having a level of >1000 µg.1–1. Echocardiographic findings were compared to 52 age-matched controls with structurally normal hearts who had either been evaluated for an innocent cardiac murmur (n=24) or volunteered (n=28) to have their heartexamined by TDE.

Echocardiography technique
Tissue Doppler echocardiography data wereacquired transthoracically with a frame rate between 96 and 158 Hertz using a 2.5 or 3.5 MHz transducer interfaced with a system V sectorscanner (G.E. Vingmed, Horten, Norway). Imaging was performed from the apex in a view equivalent to the apical four-chamber view. Care was taken to image optimally the myocardium from base to apex.

The myocardial velocities were sampled continuously from base to apex in the free wall of the right, and left ventricle, and in the ventricular septum. Recordings were made simultaneously with ECG and phonocardiogram and were stored digitally for off-line analysis. Echo Pac software (G.E. Vingmed, Horten, Norway) was used to analyse the stored myocardial Doppler data. The peak myocardialvelocities during systole (s-wave), early diastole (e-wave) and late diastole (a-wave) were measured at the base, middle and apical portion of the free walls of the right and left ventricle, and the ventricular septum.8 The isovolumic relaxation time was measured from the onset to the second heart sound to the beginning of the myocardial e-wave on the TDE tracing. A wall motion abnormality was defined as being present only, if complete reversal of the systolic or diastolic velocity vector was found.9 Recognition of the direction of myocardial velocities during the different phases of the cardiac cycle is facilitated by colour coding of the myocardial velocities,10 with reversal of wall motionvelocities being indicated by a change in colour from red to blue or vice versa (Fig. 1). Measurements of the myocardial velocities and the various time intervals were performed on three consecutive heart beats and the average of the threemeasurements was calculated. All patients were in sinus rhythm at the time of examination.



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Figure 1 Normal TDE velocity profile of the ventricular septum in a normal control displayed as both colour-coded (left side) and spectral Doppler (right side) . The myocardial velocities are sampled at the base and the apex. The systolic s-wave during ejection is directed from base to apex, the diastolic e- and a-wave are directed from apex to base with the lower velocities measured at the apex.

 
Assessment of myocardial iron load by magnetic resonance imaging
MRI was performed within 30 days of TDE using a Picker 1.5 T edge scanner (Marconi MedicalSystems, Ohio). Each scan lasted about 45 min, and included measurements of liver, heart T2*, global left ventricular function, volumes and mass using standard techniques.11 Ventricular ejection fraction was calculated from the MRI derived volumes. Iron load causes signal loss in affected tissues in MR images because iron deposits become magnetized in the scanner.12 In order to quantify the relationship between tissue signal intensity on MR images and tissue iron, we measured T2*, a relaxation parameter arising principally from local magnetic field inhomogeneities that are increased with iron deposition. This technique has been validated by comparing liver T2*and tissue iron in patients undergoing liver biopsy.7 T2*was inversely related to tissue iron (r=0.93, P<0.0001).7 In the heart we found the normal T2*to range between 20–83 ms, thus a T2*<20 ms represents an abnormal myocardial iron load. A full-thickness region of interest was measured in the LV myocardium, encompassing both epi- and endocardial regions. This was located in the septum, distant from the cardiac veins, which can cause susceptibility artefacts.7 The myocardial T2*was calculated using dedicated in-house software (CMR tools ©Imperial College).

Analysis of data
Analysis of TDE data (by M.V.) was performed blind to the results of the MRI. Similarly (L.J.A.), performing the analysis of the MRI, was blinded to the results of the echocardiographic study. Both L.J.A. and M.V. were blinded to the clinical findingsobtained by J.M.W.

Data obtained by TDE in the 52 patients and the 52 controls, and between patients with and without regional wall motion abnormalities were compared using an unpaired t-test with a P-value of <0–05, considered to represent a significant difference between groups. A chi-square test was performed to compare incidence of abnormalities of regional myocardial velocities in patients with and without myocardial iron overload. A simple regression analysis was used to compare severity of iron load and abnormal regional myocardial velocities.

Results

All controls had the characteristic pattern of myocardial velocities with an apically directed systolic velocity (s-wave) and an early (e-wave) and late (a-wave) diastolic velocity directed towards the base of the heart, with a gradual velocity decrease from base to apex (Fig. 1). In patients with thalassaemia, systolic and diastolic myocardial velocities were abnormally low in both the right and left ventricle (Tables 1 and 2) indicating a reduced global systolic function compared to controls when using TDE. However, the MRI derived ejection fraction was 66±9 (41–83)% with only two thalassaemia patients having an ejection fraction <60%, indicating preserved global function, by conventional criteria, in most patients. Overall, TDE detected regional wall motion abnormalities in 38 (73%)patients (Table 3). The majority of wall motion abnormalities (Fig. 2) were found in systole, they were associated with diastolic abnormalities in 24/38 (61%) patients. There was a positive correlation (r=039, P<0.02) between the magnitude of the velocity of the reversed s- or e-wave and myocardial iron loading but not between the length of the segment with abnormal wall motion and iron loading. Inpatients with regional wall motionabnormalities, MRI derived ejection fraction was lower than that measured in patients without wall motion abnormalities, however, in both groups it was within normal limits (Table 4).


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Table 1 Myocardial velocities in the left ventricle in patients with thalassemia (n=52) and age-matched controls (n=52)

 

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Table 2 Myocardial velocities in the right ventricle in patients with thalassenua (n=52) and age-matched controls (n=52)

 

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Table 3 Wall motion abnormalities and their location in patients with thalassaemia and T2* duration

 


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Figure 2 TDE velocity profile in ventricular septum in a patient with thalassaemia (patient 16 in Table 3). At the apex both s-wave and e-wave are reversed indicating a systolic and diastolic wall motion abnormality and there is also a reversal of colour from blue to red as further proof of the reversal of myocardial velocities.

 

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Table 4 Clinical data, iron load and therapy inpatients with and without wall motion abnormalities

 
An abnormal myocardial iron loading (T2*<20 ms) was present in 38/52 (73%) patients. We found a significant correlation between the presence of wall motion abnormalities and abnormal iron loading of the myocardium: wall motion abnormalities were present in 33/38 (88%) patients with an abnormal myocardial iron load, and in 5/14 (35%)patients with a normal T2*(P<0.04). Using MRI as the comparative ‘gold’ standard to the new technique of tissue Doppler echocardiography, thesensitivity of TDE to detect abnormal iron loading was 88%, while the specificity was 65%.

There was no significant difference in the incidence of wall motion abnormalities betweenpatients with a 1 year average serum ferritin below <1000 µg.l–1and those with a higher average serum ferritin (Table 4).

Discussion

Our data show that patients with thalassaemia have both global and regional RV and LV dysfunction on the basis of abnormal tissue Doppler derived myocardial velocities. Regional wall motion abnormalities detected by TDE can be present even in patients whose conventional indices of global systolic function, such as MRI derived ejection fraction, are within the normal range. The regional wall motion abnormalities are related to myocardial iron overload and are likely to represent evidence of iron induced myocardial dysfunction.

Previous studies found a poor correlationbetween iron load and ventricular function, but this may reflect the inadequacy of serum ferritin levels or the number of blood transfusions as predictors of myocardial iron status.6 Also, the crude nature of standard echocardio-graphic measurements previously employed is likely to have missed subtle changes in myocardial function. Conventional M-mode techniques2,3 have failed to distinguish LV function of patients with thalassaemia and iron overload from that of normal controls2 when global function was examined. However more detailed analysis of digitized M-mode echocardiographic tracings has detected abnormal segmental changes in contraction and relaxation.13 Our study confirms and extends these observations with the novel technique of TDE, which allows the evaluation of regional ventricular function.8,9

We have shown that iron loading affects systolic and diastolic function. The magnitude of systolic myocardial velocities measured by TDE at the base of the heart reflecting global long axis function14 was reduced in both LV and RV, while MR derived ejection fraction was still within the normal range. We also measured abnormal early diastolic myocardial velocities, prolonged isovolumic relaxation times, and abnormal relations between e- and a-velocities, predominantly in the RV and in some segments of the LV. Although not directly comparable to myocardial velocities, Doppler velocities across the mitral valve have been demonstrated to show similar changes i.e. an abnormal e/a velocity ratio in patients with thalassaemia major.15 The different effect of iron loading on the isovolumic relaxation time in the RV vs the LV in our cross-sectional study and the higher prevalence of wall motion abnormalities in the septum point to the fact that iron deposition in thalassaemia may affect all parts of the heart.

A previous study using endomyocardial biopsies in iron overloaded patients found no correlation between the presence of stainable iron in themyofibrils and the serum iron, transferrin or serum ferritin concentrations, emphasizing the importance of more directly assessing iron deposition in the heart.16 Clinical and experimental studies have shown that iron is deposited within myocytes rather than within the interstitium.16,17 This iron deposition in the heart is not uniform but patchy.18 This is in keeping with our observation that regional wall motion in patients with thalassaemia and iron overload is altered in the absence of global dysfunction. We found the majority of wall motion abnormalities located in the ventricular septum while the LV and RV free wall were affected less frequently. While there is no clear explanation for this observation, it is in keeping with a previous study using ultrasonic integrated backscatter in patients with thalassaemia which reported regional abnormalities in the septum and the left ventricular free wall.19 The latter study, like ours, included younger patients at an earlier stage of the disease and it may be possible that at an early stage the iron is predominantly deposited in the septum while at a later stage other areas become affected.

Limitations of this study
We were able to demonstrate abnormalities of ventricular function in patients who, by conventional assessments of iron load, were well controlled and had no history of cardiac decompensation. Resting measurements were performed in this study, so that it is possible that stress tests may have amplified disturbances in function or detected abnormalities in patients with normal resting values. Technetium scintigraphy at rest and exercise and dobutamine stress echocardiography have both shown abnormal exercise responses in patients with normal resting studies.2,20

In vivo assessment of myocardial iron concentration remains difficult and controversial. We have used MRI T2*, as a close correlation between liver T2*and liver biopsy has been demonstrated.7 We now demonstrate a relation between myocardial T2*and functional abnormalities in the myocardium assessed by an independent technique: TDE, which can non-invasively detect myocardial dysfunction. TDE is simple, repeatable and can be performed during interventions, making it an attractive method to follow patients in longitudinal studies. Furthermore it should be more widely available than MR imaging, especially in those countriesfacing the greatest burden of thalassaemiapatients. Using this echocardiographic technique, the effects of therapy, especially iron chelation, can be monitored and modified according tothe detection of myocardial involvement, thuspotentially improving the outlook of patients with thalassaemia.

Conclusions

From our data we conclude that clinically asymptomatic patients with myocardial iron overload have abnormal global longitudinal function as well as wall motion abnormalities which may be a reflection of early myocardial damage. This early damage is detectable by a widely applicable echocardiographic method which may be more appropriatefor those developing countries with a population affected by thalassaemia.

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