This study shows that in young adults with β thalassaemia but no clinical signs of cardiopulmonary involvement, and with a mean pretransfusional haemoglobin concentration of around 9 g/dl, there are abnormalities of left ventricular morphology and systolic and diastolic function. In particular, there is an increase in left ventricular volumes, mass, stroke volume, and cardiac index, with decreased systemic vascular resistance, explaining the decreased systolic and diastolic blood pressure. The increased volume load is a reflection of the Frank–Starling mechanism and an increase in heart rate. All these findings are in agreement with those reported by others and are related to the increased cardiac output caused by the chronic anaemia.3,21
Our study also shows a decrease in left ventricular systolic performance owing to an increase in the afterload and a reduced contractile state, which is probably secondary to iron toxicity.22–24
Waldes-Cruz and colleagues demonstrated abnormalities of left ventricular systolic and diastolic function in asymptomatic children with β thalassaemia, using computer assisted echo studies.22
Borow and colleagues reported an abnormal left ventricular end systolic pressure/dimension relation in asymptomatic young adults with β thalassaemia, showing normal indices of global systolic performance.23
Others have reported early cardiac dysfunction in asymptomatic β thalassaemic patients with chronic iron overload, using stress radionuclide angiography. The stress induced alterations of left ventricular systolic performance showed a correlation with the total amount of blood transfused in these patients. Even in patients with few blood units transfused, an abnormal response of the left ventricular ejection fraction to exercise was found, while the haemoglobin concentration was not predictive of left ventricular performance.24
Moreover, in asymptomatic patients with β thalassaemia submitted to an aggressive iron chelation regimen, a decrease in serum ferritin was associated with an increase in the left ventricular ejection fraction during stress testing.25
In our study, we found a weak but significant correlation between left ventricular ejection fraction and serum ferritin concentration. Patients with a high ferritin concentration (> 2500 ng/ml) had a lower ejection fraction than patients with a low ferritin concentration (< 1000 ng/ml). No other haematological data correlated with the echocardiographic findings.
In 1994 Olivieri and colleagues, in a prospective clinical study,26
found that the cardiovascular prognosis in thalassaemic patients was excellent if serum ferritin concentrations were maintained below 2500 ng/ml. This value has been considered a “safe” concentration.26
Our study confirms this assumption, demonstrating the importance of a low ferritin concentration for the preservation of left ventricular mechanics. The higher mean age of our patients is further confirmation of a significant improvement not purely related to quality of life. This probably reflects a more aggressive treatment and the further lowering of the ferritin concentration in our study population. We suggest that a serum ferritin value of less than 1000 ng/ml should be considered the ideal goal of any therapeutic schedule. The value of starting this therapeutic approach early and maintaining good compliance has been documented before.26,27
Reports concerning left ventricular diastolic function in patients with β thalassaemia are somewhat conflicting.2–4
In 1991, Spirito and colleagues reported a restrictive pattern of transmitral flow in a group of young adults with normal systolic function.2
In contrast, no alteration in left ventricular compliance was reported in the early stage of the disease by Kremastinos and associates.3,4
The filling pattern previously reported was explained by increased volume overload caused by the hyperdynamic state.3,28
A strongly restrictive pattern of transmitral flow was reported only in the final stages of the disease, as in the final stages of dilated cardiomyopathies.2,3,29,30
In agreement with Kremastinos and colleagues,3
we have shown in our group of asymptomatic young thalassaemic adults that there is normal left ventricular compliance, and the increase in velocities and integrals of the mitral and pulmonary venous flow could be explained by the high cardiac output state.
Our study, which involved a large and clinically homogeneous group of patients with β thalassaemia following an aggressive transfusion and iron chelation treatment regimen, confirms the primary role of the high cardiac output state in the pathogenesis of most of the echo Doppler findings in this condition. However, there is no consensus over the optimal haemoglobin concentration required to reduce the volume overload, and consequently the optimum chelation dose for the individual patient. Our study further underlines the importance of reducing body iron stores, as a correlation between serum ferritin and left ventricular mechanics has been confirmed.
Thus several factors are involved in the pathogenesis of the so called “β thalassaemic cardiomyopathy”. The first factor is the significant volume overload imposed by the chronic anaemia,3,4
and this has also recently been demonstrated in patients affected by thalassaemia intermedia.31
More aggressive transfusion treatment could reduce the role of this factor, though it has the disadvantage of a further increase in the iron load. The second factor is iron toxicity, although the mechanisms involved in this are not universally agreed. However, cardiac iron deposits surely represent a late event, and their amount has so far not proved easy to estimate.32
A third factor is the possibility that infectious myopericarditis plays a significant role in the pathogenesis of severe left ventricular dysfunction.33,34
Further studies are required to clarify the role of this complication, as bacteriological and virological studies have revealed no causative factor in the majority of cases reported so far, though immune or genetic mechanisms have recently been proposed.34,35