**2.1. Epidemiology of radiation-induced CVD**

over both genders and adult ages to reflect the radiation burden to an average human adult [18, 19]. Examples of effective doses associated with different sources of ionizing radiation

Short after the discovery of ionizing radiation by Röntgen in 1895, its detrimental effects became apparent, and people tried to protect themselves [24]. Nowadays, the International Committee on Radiological Protection (ICRP) and the US National Council on Radiation Protection and Measurements (NCRP) aim to protect people by advising means for achieving

The major question that keeps radiation protection bodies busy and that became the foundation of radiation protection guidelines worldwide is "How much is harmful?" This question is particularly relevant for low-dose exposures for which health impact is not yet fully elucidated. Although a large number of epidemiological and radiobiological studies have been performed to date in order to investigate the effects of low doses of ionizing radiation [26–47], accurate risk assessment is not yet available [18]. Current guidelines for protection against low-dose radiation are based on cancer risk estimates from epidemiological studies. As discussed further, cohorts include atomic bomb survivors, occupationally exposed people, patients (diagnostics or therapeutics), and environmentally exposed people [48]. In general, an excess cancer

**Source Effective dose (mSv)\***

Dental X-ray 0.005 Radiography of the chest 0.1 One return flight (New York-London) 0.1 Radiography of the abdomen 1.2 CT of the head 2 Natural background (per year) 2.4 Mammography 3 CT of the chest 7 CT of the abdomen 6–10 CT of the pelvis 8–10 Coronary CT angiography 12 Myocardial perfusion study 10–29 Myocardial viability study 14–41 Annual occupational dose limit 20

Radiotherapy (delivered in fractions) 40,000–70,000

**Table 1.** Representative effective doses associated with different sources of ionizing radiation.

Doses are whole-body doses, except those of medical exposure, which are delivered to a specific organ. CT, computed

\*

tomography; Sv sievert [7, 19–23]

are presented in **Table 1**.

**1.3. Protection against radiation exposure**

368 Endothelial Dysfunction - Old Concepts and New Challenges

this, e.g., regulatory and guidance limits [18, 25].

Current predictions indicate that in Western countries almost one of three people will develop cancer during their lifetime [56]. About 50–60% of all cancer patients will undergo radiotherapy with radiation doses averaging 1.8–2 Gy per fraction [57]. During the radiotherapeutic treatment of tumors located in the mediastinal region of the human body (breast, lung, and esophageal cancers), the heart and its blood vessels incidentally receive a part of the radiation dose [46]. Exposure of the cardiovascular system to these therapeutic doses is known to be associated with CVDs. The first epidemiological evidence of this association came from radiation-treated Hodgkin's lymphoma survivors in the 1960s. In a study of 258 Hodgkin's disease patients followed for a median of 14.2 years (range 0.7–26.2) after radiotherapy, cumulative risk for ischemic event increased from 6.4% (95% confidence interval (CI), 3.8 ± 10.7) at 10 years to 21.2% (95% CI, 15 ± 30) at 20–25 years after radiotherapy treatment. Risk for myocardial infarction was 3.4% (95% CI, 1.6 ± 7.0) at 10 years and 14.2% (95% CI, 9 ± 22) at 20–25 years, and risk for ischemic cardiac mortality was 2.6% (95% CI, 1.1 ± 6.1) at 10 years and 10.2% (95% CI, 5.3 ± 19) at 25 years (**Figure 2A**) [58]. Cardiac fibrosis, which causes cardiac dysfunction, arrhythmias, and heart failure, is also seen in Hodgkin's lymphoma survivors but is rather the result of the use of anthracyclines [59]. Radiation-induced cardiovascular disorders are based rather on the damage to the blood vessels. Later, in the study of Darby et al., 2168 breast cancer patients were followed between 5 and more than 20 years after radiotherapy. It was found that women irradiated for left breast cancer (estimated mean heart dose 6.6 Gy) had higher rates of major coronary events than women irradiated for right breast cancer (estimated mean heart dose 2.9 Gy; P = 0.002). Excess relative risk (ERR), a measure that quantifies how much the level of risk among persons with a given level of exposure exceeds the risk of nonexposed persons [60] for major coronary events was 7.4% per Gy (95% CI, 2.9–14.5) when all follow-up times and all breast cancer patients were included (**Figure 2B**) [54].

When the heart receives a radiation dose lower than 0.5 Gy, epidemiological evidence is less strong than that for higher doses. The most informative cohort in this respect is composed of Japanese atomic bomb survivors. It is of high value for low-dose epidemiology as a source for risk estimation due to its large size, the presence of both sexes and all ages, and because irradiated people have well-characterized individual dose estimates [36]. Studies in occupationally exposed individuals are also of interest as they generally involve relatively low doses received during repeated exposures. Examples of such cohorts are nuclear industry workers from 15 countries (the 15-country study) [37], the UK National Registry for Radiation Workers [38], the National Dose Registry of Canada [39], the Chernobyl liquidator cohort [40], and the Mayak cohort [41–43]. The last cohort is composed of workers from Mayak PA, the first and largest Russian nuclear factory for plutonium production where the majority of workers were exposed to ionizing radiation during the first period of operation [61]. In addition, data can also be acquired from environmentally exposed groups, such as settlements located at the vicinity of

Selected Endothelial Responses after Ionizing Radiation Exposure

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When taking into account all epidemiological data on CVD effects of ionizing radiation, a small but highly statistically significant ERR of 0.09 per Gy (95% CI, 0.07–0.12) was observed at doses higher than 0.5 Gy [35]. In addition, ERR of CVD mortality was estimated at 0.08 (95% CI, 0.04–0.12). In other words, receiving 1 Gy of ionizing radiation to the heart and its blood vessels increases the risk of CVD mortality with 8% in comparison to nonexposed people. This assumed risk is rather large and may therefore have serious implications for public health. Indeed, considering the high background rate of CVD, the absolute number of excess cases could be substantial [62]. In order to find an association between low-level radiation exposure and CVD risk in a general unselected population, this meta-analysis was extended by Little et al. [55]. When taking into account 717,660 individuals from the Japanese atomic bomb survivor and occupational and environmental exposure studies listed above, a statistically significant ERR coefficient of 0.10 (95% CI, 0.05–0.15) for coronary artery disease was observed as a result of exposure to low-level radiation more than 5 years prior to death [55]. A linear association between ERR and radiation dose was assumed even in the low-dose range, because there was little evidence of nonlinearity in the dose-response curves for CVD in Japanese atomic bomb survivors [34, 63] and in Mayak workers [41]. Authors further argued that the consistency of ERR/Gy between Japanese atomic bomb survivors with moderate radiation doses [34, 63] and occupational cohorts with low doses could be used to support the notion of a linear relationship between ERR of CVD mortality and low doses of ionizing radiation [55]. In a recent third analysis of the Life Span Study cohort of atomic bomb survivors with 105,444 subjects, the shape of the dose-response curve for solid cancer incidence was found significantly different among males and females (P = 0.02). For females, dose-response was consistent with linearity, but for males dose-response best fitted a linear-quadratic model [64]. If this were to be confirmed, the overall excess risk of CVD-associated mortality after exposure to low doses of radiation would be about twice that associated to radiation-induced cancers, which ranges from 4.2% to 5.6% per Sv for the cohort populations discussed above [55, 65] and

Following radiotherapy of the thoracic part of the human body for mediastinal lymphoma, breast, lung, and esophageal cancers, the heart incidentally receives a part of the therapeutic dose [46].

the Techa River [44] and the Semipalatinsk nuclear test area [45].

would even be different between both sexes.

**2.2. Pathophysiology of radiation-induced CVD**

Additional proofs of increased risk of CVDs after high-dose exposure were provided during the follow-up of Japanese atomic bomb survivors. During a 53-year follow-up of 86,611 members of the Life Span Study cohort, excess relative risk of death from heart disease per Gy was 0.14 (95% CI 0.06–0.23) (**Figure 2C**) [34]. Although there is a large number of epidemiological studies showing a clear excess of CVD risk above 0.5 Gy, they are of limited use for quantitative risk assessment, because individual dosimetry has yet to be performed [35]. In addition, even if an adverse effect can be evidenced at relatively high doses of ionizing radiation, mechanisms by which therapeutic doses affect the cardiovascular system are still not completely understood [28].

**Figure 2.** Epidemiological evidence for an increased risk of CVDs after exposure to ionizing radiation. (A) Cumulative risk curves for the occurrence of cardiac events in Hodgkin's lymphoma survivors [58]. (B) Rate of major coronary events according to mean radiation dose to the heart given during breast cancer radiotherapy, as compared with the estimated rate with no radiation exposure to the heart [54]. (C) Excess relative risk for death from heart disease in Japanese atomic bomb survivors. Shaded area is the 95% confidence region for the fitted lines [34].

When the heart receives a radiation dose lower than 0.5 Gy, epidemiological evidence is less strong than that for higher doses. The most informative cohort in this respect is composed of Japanese atomic bomb survivors. It is of high value for low-dose epidemiology as a source for risk estimation due to its large size, the presence of both sexes and all ages, and because irradiated people have well-characterized individual dose estimates [36]. Studies in occupationally exposed individuals are also of interest as they generally involve relatively low doses received during repeated exposures. Examples of such cohorts are nuclear industry workers from 15 countries (the 15-country study) [37], the UK National Registry for Radiation Workers [38], the National Dose Registry of Canada [39], the Chernobyl liquidator cohort [40], and the Mayak cohort [41–43]. The last cohort is composed of workers from Mayak PA, the first and largest Russian nuclear factory for plutonium production where the majority of workers were exposed to ionizing radiation during the first period of operation [61]. In addition, data can also be acquired from environmentally exposed groups, such as settlements located at the vicinity of the Techa River [44] and the Semipalatinsk nuclear test area [45].

When taking into account all epidemiological data on CVD effects of ionizing radiation, a small but highly statistically significant ERR of 0.09 per Gy (95% CI, 0.07–0.12) was observed at doses higher than 0.5 Gy [35]. In addition, ERR of CVD mortality was estimated at 0.08 (95% CI, 0.04–0.12). In other words, receiving 1 Gy of ionizing radiation to the heart and its blood vessels increases the risk of CVD mortality with 8% in comparison to nonexposed people. This assumed risk is rather large and may therefore have serious implications for public health. Indeed, considering the high background rate of CVD, the absolute number of excess cases could be substantial [62]. In order to find an association between low-level radiation exposure and CVD risk in a general unselected population, this meta-analysis was extended by Little et al. [55]. When taking into account 717,660 individuals from the Japanese atomic bomb survivor and occupational and environmental exposure studies listed above, a statistically significant ERR coefficient of 0.10 (95% CI, 0.05–0.15) for coronary artery disease was observed as a result of exposure to low-level radiation more than 5 years prior to death [55]. A linear association between ERR and radiation dose was assumed even in the low-dose range, because there was little evidence of nonlinearity in the dose-response curves for CVD in Japanese atomic bomb survivors [34, 63] and in Mayak workers [41]. Authors further argued that the consistency of ERR/Gy between Japanese atomic bomb survivors with moderate radiation doses [34, 63] and occupational cohorts with low doses could be used to support the notion of a linear relationship between ERR of CVD mortality and low doses of ionizing radiation [55]. In a recent third analysis of the Life Span Study cohort of atomic bomb survivors with 105,444 subjects, the shape of the dose-response curve for solid cancer incidence was found significantly different among males and females (P = 0.02). For females, dose-response was consistent with linearity, but for males dose-response best fitted a linear-quadratic model [64]. If this were to be confirmed, the overall excess risk of CVD-associated mortality after exposure to low doses of radiation would be about twice that associated to radiation-induced cancers, which ranges from 4.2% to 5.6% per Sv for the cohort populations discussed above [55, 65] and would even be different between both sexes.
