Cardiomyopathy is a condition in which heart muscle becomes damaged and dysfunctional due to a variety of causes, including exposure to ionizing radiation such as one might experience in cancer radiotherapies or in accidental, terrorist, or military nuclear events. Japanese survivors of the Hiroshima and Nagasaki atomic bombings have marked increases in heart and cardiovascular disease, as do survivors of medical radiotherapies in which the heart becomes exposed to radiation. Unfortunately, there are no accepted recommendations for how to prevent or treat radiation induced heart disease and cardiomyopathy. Expanding global threats which could lead to malicious military or terrorism related radiation injury are considerable and relevant in today’s world.
The biological pathways involved in radiation induced cardiomyopathies are poorly understood. DNA can be modified chemically by methylation leading to an alteration in the way in which cells and tissues function. Changes in DNA methylation have been recently identified as a potential factor in the development of cardiomyopathy induced by high blood pressure. There are treatments which can alter DNA methylation systemically using specific inhibitors which could provide a strategy for intervention. The importance of myocardial DNA methylation in radiation induced cardiomyopathy and heart disease is not known.
The proposed project seeks to identify the delayed effects of radiation exposure of the heart on myocardial DNA methylation profiles in non-irradiated and irradiated non-human primate (NHP) survivors, which are excellent models of human health and known to develop cardiomyopathies similar to those seen in people. The central hypothesis of the proposed work is that radiation exposure to the heart will induce specific and long lived alterations in DNA methylation which may play important roles in myocardial fibrosis and the future development of cardiomyopathy. The proposed project will determine the effects of radiation exposure on myocardial DNA methylation, and relationships between these changes and adverse effects of radiation on the heart. The proposed studies are innovative, there are no published studies which have evaluated the effects of ionizing radiation on global myocardial DNA methylation profiles and the relationships of the myocardial methylome to cardiomyopathy or myocardial fibrosis. This work will provide new insights into potential mechanisms by which radiation produces long term delayed effects on the heart, and should help to identify pathways for interventions to delay or prevent radiation induced cardiomyopathies in individuals exposed to malicious, accidental, or medical ionizing radiation. In addition, these studies will be economical, making use of already available nonhuman primate myocardial tissue and data which will complement the proposed outcomes. The findings will help inform future grant applications to understand cardiomyopathy and develop and test new interventions for prevention and treatment.

CDMRP Discovery Award 12662528

2019-05-01

2021-04-30