This CMR multicenter study is the first that evaluated the distribution, clinical correlates, and diagnostic capability of the LVGFI, a relatively new marker of cardiac performance.
We did not find a significant reduction of the mean LVGFI or LVEF in TM patients when compared with control subjects of identical age and sex distribution, while TM was associated with significantly higher LV volumes. Despite regular transfusion therapy, TM represents a chronically anaemic condition, characterized by an increase in blood volumes (increased preload) and a decrease in systemic vascular resistance (decreased afterload) [35]. The anatomical–functional expression of this hemodynamic state is the enlargement of cardiac cavities and the increase of LVEF [36–38]. Myocardial iron overload is initially expressed as diastolic LV dysfunction but in end stage disease it may increase ventricular dimensions and decrease systolic function [39, 11]. Indeed, when we categorized our patients based on the presence of significant MIO, both LVEF and LVGFI were reduced in TM patients with MIO versus patients without MIO and healthy subjects, while there was no difference between patients without MIO and healthy subjects.
In TM patients, as in healthy subjects and in other patient populations, the male sex was associated with lower values of LVGFI, which can be explained by the different morphology of male and female hearts [22, 40, 41].
Besides male sex, diabetes, significant MIO, and replacement myocardial fibrosis were associated with worse LVGFI.
It should be recognized that global heart T2* values showed only a weak correlation with LV function markers, likely because, although iron could be removed by chelation treatment [42, 43], the induced heart damage could be progressive and not totally reversible. Moreover, heart damage in thalassemia does not result only from iron overload, but other factors like nutritional deficiencies, genetic factors, diabetes, and other endocrinopathies can play a role [44, 16, 45, 46]. Anyway, LVGFI seems to be more closely related to cardiac iron burden and distribution than LVEF. Our findings can be explained by the fact that although the LVGFI is strongly related to LVEF, it carries additional data. In fact, it includes information on physiological adaptation as well as pathological remodelling by measures of both cavity size and myocardial mass [20]. Increased thickness of the ventricular wall is one of the first, and still reversible, cardiac alterations due to iron deposition in the myocardium [47]. The increase in LV wall thickness may be explained by the fact that iron deposition in the myocytes causes them to hypertrophy. Later, with increasing iron overload, left dilated cardiomyopathy develops and ventricular function becomes impaired [47, 48]. In fact, significant LVEF changes appear later and are preceded by significant compensatory modifications in LV mass and volumes to preserve systolic function. In presence of an increased LV mass and increased relative wall thickness, the LVGFI decreases while the LVEF remains unchanged since it does not account for LV mass. Only in presence of an increase in the size of the ventricular cavity both functional indices are significantly decreased. However, the LVGFI is still more decreased than LVEF.
In agreement with previous studies, we confirmed the lack of correlation between myocardial fibrosis and heart iron [49, 30]. Conversely, our findings suggest that myocardial fibrosis can have a negative impact on ventricular remodelling.
Our study clearly demonstrated for the first time an association between LVGFI and HF in TM. Importantly, the LVGFI was shown to provide a superior discriminatory ability compared with the LVEF, suggesting that the LVGFI is a useful functional parameter of the LV also in the thalassaemic population. Apart from the benefit of the inclusion of structural aspects of cardiac remodelling, another contributory factor to the improved performance of LVGFI may be its association with diabetes mellitus. In a large retrospective historical TM cohort, diabetes was associated with a significantly higher risk of myocardial fibrosis, HF, and hyperkinetic arrhythmias, independently from MIO [44].
Limitations
A major limitation of this study is that it is a cross-sectional analysis. Prospective studies on large cohorts of TM patients are recommended to evaluate if LVGFI is a strong, independent, antecedent predictor of HF and if it can provide incremental prognostic value in comparison with LVEF.
We did not measure myocardial deformation (strain), which offers a more accurate and direct measure of myocardial function than EF [50]. Although feature tracking CMR allows quantification of myocardial deformation on routine SSFP cine images, the dedicated post-processing FT software packages were not available in the MIOT centers.