91 Late cardiac toxicity in survivors of esophageal cancer healthy, study population[39]. In this paper, both shorter QRS complexes and lower voltages were seen in linear correlation with age and ECV values(supplementary 3). In addition to the shorter QRS complex we indeed found a microvoltage ECG in 2 (vs 0) of the irradiated patients. Our results are therefore in line with these findings. Lower voltages ECG’s can be caused by, for example, pericardial effusion, pericardial fibrosis and by an infiltrating cardiomyopathy[40], which are known complications after irradiation of the heart[41,42]. The thinner septum between the ventricles may actually also be in line with these findings as thinner myocardial walls(fibrosis) may result in lower voltage ECG’s. These findings could be relevant as prognosis in otherwise healthy adults with low voltage ECG’s is worse[43] We did correct for age difference between the groups in these analyses because age has been well recognized as a prognostic factor for cardiac comorbidities. We realized there was a difference in interval after treatment as well. Theoretically, this may influence the number of cardiac events, but this did not seem to change significance levels and therefore did not have an effect in this population. It should be stressed that this was a relatively small cross sectional hypothesisgenerating pilot study and therefore neither definitive conclusions nor causality based on these results can be drawn. Furthermore, while the patients group of this study were treated using 3-dimensional radiotherapy, current techniques such as IMRT or proton therapy have reduced the dose to critical organs such as the heart, and thus, in future studies, lower toxicity rates would be expected. However, the clinical diagnosis of AF and ECG changes of the heart, as described in the current study, can be related to radiation dose dependent myocardial fibrosis as seen on MRI. These clinically relevant findings can provide further insight into the mechanisms behind radiation induced cardiac complications, which need to be further explored. More information is needed on consequent clinical symptoms and cardiac dysfunction in order to estimate the possible benefit of primary and secondary preventive measures. In conclusion we hypothesize that in EC patients, radiation-induced myocardial fibrosis plays a central role in cardiac toxicity leading to AF, conduction changes and ultimately to decreased role functioning. The results emphasize the need to verify these findings in larger cohorts of patients. 6
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