The heart has traditionally been considered a radio-resistant organ that would be unaffected by cardiac doses below about 30 Gray. During the last few years, however, evidence that radiation-related heart disease can occur following lower doses has emerged from several sources. These include studies of breast cancer patients, who received mean cardiac doses of 3–17 Gray when given radiotherapy following surgery, and studies of survivors of the atomic bombings of Japan who received doses of up to 4 Gray. At doses above 30 Gray, radiation-related heart disease may occur within a year or two of exposure and risk increases with higher radiotherapy dose, younger age at irradiation, and the presence of conventional risk factors. At lower doses the typical latent period is much longer and is often more than a decade. However, the nature and magnitude of the risk following lower doses is not well characterized, and it is not yet clear whether there is a threshold dose below which there is no risk. The evidence regarding radiation-related heart disease comes from several different disciplines. The present review brings together information from pathology, radiobiology, cardiology, radiation oncology and epidemiology. It summarises current knowledge, identifies gaps in that knowledge, and outlines some potential strategies for filling them. Further knowledge about the nature and magnitude of radiation-related heart disease would have immediate application in radiation oncology. It would also provide a basis for radiation protection policies for use in diagnostic radiology and occupational exposure.

Analogs of vitamin E (tocols) are under development as radioprophylactic agents because of their high efficacy and lack of toxicity. Gamma-tocotrienol (GT3) is of particular interest because, in addition to being an antioxidant, it also inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase and accumulates to greater extent in endothelial cells than other tocols. We addressed in vivo whether HMG-CoA reductase inhibition contributes to the radioprotection conferred by GT3. Groups of mice were treated with vehicle, mevalonate (the product of the reaction catalyzed by HMG-CoA reductase), GT3 alone or GT3 in combination with mevalonate. Lethality and standard parameters of injury to the hematopoietic, intestinal and vascular/ endothelial systems were assessed after exposure to total-body irradiation. GT3 improved postirradiation survival and decreased radiation-induced vascular oxidative stress, an effect that was reversible by mevalonate. GT3 also enhanced hematopoietic recovery, reduced intestinal radiation injury, and accelerated the recovery of soluble markers of endothelial function. These parameters were not reversed by mevalonate co-administration. Our data confirm GT3's radioprophylactic properties against hematopoietic injury and, for the first time, demonstrate benefits in terms of protection against gastrointestinal and vascular injury. The radioprotective efficacy of GT3 against vascular injury is related to its properties as an HMG-CoA reductase inhibitor.

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Inhibitors of Rho kinase (ROCK) are a relatively new class of drugs with potential benefits in oncology, neurology, and fibrotic and cardiovascular diseases. ROCK-inhibitors modulate many cellular functions, some of which are similar to the pleiotropic effects of statins, suggesting additive or synergistic properties. Studies to date have used compounds which inhibit both isoforms of ROCK, ROCK1 and ROCK2. This study was designed to compare gene expression profiles of atorvastatin with the newly developed ROCK2-inhibitor SLx-2119 in primary cultures of normal human endothelial cells, smooth muscle cells, and fibroblasts. Cells were treated with each compound for 24 hours, after which total RNA was isolated and genome-wide gene expression profiles were obtained with Illumina arrays. Because of the known effect of statins on the actin cytoskeleton and on connective tissue growth factor (CTGF), a prominent growth factor involved in tissue fibrosis, the effects of SLx-2119 and atorvastatin on the actin cytoskeleton and CTGF mRNA were also examined in cultures of smooth muscle cells with a fibrotic phenotype, isolated from biopsies of human intestine with radiation-induced fibrosis. Although SLx-2119 and atorvastatin affected expression of genes belonging to the same biological processes, individual genes were mostly different, consistent with synergistic or additive properties. Both SLx-2119 and atorvastatin reduced CTGF mRNA and remodeled the actin cytoskeleton in fibrosis-derived smooth muscle cells, suggesting that both compounds have anti-fibrotic properties. These results form the basis for further studies to assess the possible therapeutic benefit of combined treatments.