This study demonstrates the subclinical impairment of cardiac left and in particular right function, and vascular function in childhood ALL survivors treated with anthracycline-based regimens.
The assessment of RV function recently gained increasing interest within cardio-oncology due to its role in predicting the occurrence of heart failure [31–34]. In our sample of ALL childhood survivors, subclinical alterations of the RV function were outlined by the higher values of right TEI index and lower TAPSE measurement. Interestingly, to higher cumulative doses of anthacyclines corresponded significantly lower values of TAPSE. Moreover TAPSE values < 18 mm succeeded in distinguish between patients and controls with high sensitivity and specificity (100% and 89.2%, AUC: 0.966, p < 0.0001). To our knowledge such intriguing result has not been reported before. Christiansen et al.  found reduced values in TAPSE in adult survivors of childhood malignant lymphoma or ALL who had been exposed to anthracyclines, mediastinal radiotherapy, or both. Particularly, a global reduction in RV function, as outlined by alterations also in fractional area change, peak systolic tricuspid annular velocity, and free wall strain, was observed. In line with our results, Christiansen et al. found no variations in term of right diastolic function between ALL patients and controls . Cardiotoxicity has been associated mainly to anthracycline doses > 300 mg/mq . However, signs of cardiotoxicity have been reported also with lower anthracycline doses of 100 mg/mq . In the present study anthracycline doses varied from 210 mg/mq to 350 mg/mq, therefore some cardiotoxicity might be expected in our sample. Bayram et al.  observed reduced right ventricle myocardial velocities, as assessed by TDI, in childhood leukemia survivors treated with low-dose of anthracyclines, thus deriving the impairment in systolic and diastolic function of the cardiac chamber, but do not provide any data about right TEI index. Interestingly, Kocabaş et al.  outlined the progressive increase in right TEI index with the increase in cumulative anthracycline doses. Although our study did not demonstrate the correlation between right TEI index increase and cumulative dose, the identification of progressive decrease in TAPSE with the increase in cumulative anthracycline doses confirmed the impairment in right ventricle function in ALL survivors. Indeed, patients treated with anthracyclines were reported to show impairment in right ventricular systolic and diastolic functional reserves when they underwent stress echocardiography; thus, they had subtle alterations in right cardiac chamber which can be exacerbate from stress [37,38]. All of these findings should be taken into account as the RV function seems to be a stronger predictor of developing or worsening heart failure than LV function .
Previous studies focused on the remodeling of left cardiac chambers during chemotherapy [8–10,29].
A worsening of LV function was observed in 7% of ALL patients after a mean period of 6 years after chemotherapy . Conversely, in our study, we did not observe statistically significant differences in terms of LVEF between ALL patients and controls. However, ALL patients showed higher values in left TEI index than controls, which can be considered an early sign of systo-diastolic alteration in left cardiac chambers. Particularly, left TEI index values > 0.38 may distinguish ALL survivors from healthy controls. This finding is in agreement with previous literature data [35,41].
We did not demonstrate alterations in vascular morphology in ALL survivors as compared to controls. Mean IMT and APAO were similar between the two groups. ALL survivors showed a statistically significant decrease in endothelial function as expressed by FMD. Derangement in endothelial function after anthracycline treatment has been previously reported in cancer survivors [3,42–47]. Jenei et al.  outlined the occurrence of both endothelial dysfunction and increased aortic stiffness in long term survivors of childhood cancer, both related to cumulative anthracycline dose (in mg/m2). Long et al.  confirmed the reduction in FMD values and subclinical left ventricle diastolic dysfunction during exercise stress in patients treated with anthracyclines. In our study we did not find any correlation of vascular parameters with different cumulative doses of anthracyclines.
Furthermore, when planning the follow up studies for such a growing population of childhood ALL survivors one more consideration should be given: although multimodality diagnostic and imaging (see magnetic resonance, nuclear imaging) represent essential tools to study preclinical heart injury, echocardiography is a simple imaging tool in everyday practice to monitor clinical cardiotoxicity, in order to recognize the preclinical changes.
Finally, as regard to the metabolic markers of endothelial dysfunction, namely HMW-AD, endothelin-1 and insulin resistance , in our study population we confirmed the reported data on impaired metabolic profile in young survivors of ALL , however we did not find any correlations with cardiovascular parameters and total doses of anthracyclines.