**3. Pathophysiological mechanisms of RRHD**

The detailed pathogenesis of RRHD has been well reviewed [12, 31]. Overall, the endothelial system of blood vessels, particularly the arteries seem to be the critical target structures. After radiation, early functional alterations might include the pro-inflammatory responses and other changes, followed by slow progression [31, 32]. Although experimental animal models will help to elucidate the possible cellular and molecular mechanisms of RRHD, the results from various animals might be species-specific, and caution should be used in extrapolating to humans. In cancer patients, radiation induces macro- and microvascular injury. The former accelerates age-related atherosclerosis and leads to coronary artery disease after several years or decades due to reduced blood flow to the radiated myocardial territory. On the other hand, the latter reduces capillary density and results in decreased vascular reverse, which usually occurs within several months after RT and has only subclinical manifestations [12].
