28 Chapter 2 Most of the presented imaging studies showed wall motion disorders and changes in metabolism of the myocardium in the higher radiation dose areas. These changes are in line with results from autopsy and animal studies showing damage to microvasculature, focal ischemia and fibrosis.[22] Although these changes did not result in decreased LVEF, changes in end diastolic volume, stroke indices and heart rate were observed. The LVEF may underestimate the actual cardiac damage because of the compensatory reserve of the myocardium that enables adequate ventricular outcome even when part of the myocardium dysfunctions. Reduced end diastolic volumes are known to precede a decline of the ejection fraction.[27] As imaging studies were performed shortly after treatment, these later changes were not observed. Animal studies in mice showed progressive malfunctioning of mitochondria and progressive fibrosis in the myocardium at 40 weeks after treatment.[28,29] These changes did not result in changes in cardiac function. However, in the high dose group, a significant proportion of the mice died suddenly during follow up. These sudden deaths may imply that compensatory mechanisms may not maintain cardiac function for a longer period of time.[30] Additional clinical imaging studies at later time points after treatment as well as other cardiac functional assessments are required to get more insight into the pathophysiological mechanisms of cardiac toxicity and thus should be included in future research. Evidence regarding radiation induced cardiac toxicity is available from studies in other tumor sites with high rates of cardiac death and morbidity in irradiated patients with long term follow up.[1,31,32] Most of these articles reported frequent late or very late side effects. The studies presented in this review suggest earlier toxicity with events in the first two years after treatment. Recently, Darby et al.[1] reported on the relationship between radiation dose and major cardiac events among breast cancer patients and compared them with a population-based matched control group. They found 44% of the events in the first 10 years, with no significant trend in time. In that study, the estimated mean dose to the heart was only 4.9 Gy, which is much lower than that observed among patients treated for esophageal cancer. They observed an increase in the relative risk for ischemic heart disease of 7.4% per 1 Gy mean heart dose. There was no suggestion the increase in risk was less pronounced in the higher dose group (mean dose above 10 Gy). Interestingly, they found the mean heart dose to be more relevant for ischemic events than the dose to the left anterior descending coronary artery, but as dose reconstruction in such a small organ is less reliable as shown by Lorenzen et al, this remains to be confirmed by others.[33]
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