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

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

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].

included (**Figure 2B**) [54].

370 Endothelial Dysfunction - Old Concepts and New Challenges

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]. As indicated in the epidemiology section, high-dose radiation exposure of the heart and its vessels is associated with a risk of radiation-induced CVD [34, 54, 55]. In this context, coronary artery disease is considered to be the major cardiovascular complication [28, 30, 54]. Two studies provide molecular and cellular mechanisms accounting for increased morbidity and mortality of coronary artery disease following radiation exposure. First, radiation can influence the pathogenesis of age-related atherosclerosis, thereby accelerating the development of atherosclerosis in coronary arteries [28]. Growing atherosclerotic plaques narrow the blood vessel and hamper the blood stream (**Figure 3**). Second, damage to the heart microvasculature can reduce blood flow to the myocardium, causing myocardial ischemia, which promotes acute infarction [30]. Because endothelial activation and dysfunction are major causes of atherosclerosis, much of the current radiobiological research is exploring the molecular and phenotypic effects of ionizing radiation in endothelial cells in the context of radiation-induced CVD [66, 67]. It should be noted, however, that there are also other clinical manifestations of radiation-related CVD, such as pericarditis, congestive heart failure, and heart fibrosis [30, 68, 69]. Radiation-induced pericarditis is caused by damage to the cardiac microvascular network in combination with fibrosis of cardiac venous and lymphatic channels. This ultimately leads to accumulation of a fibrin-rich exudate in the pericardium, causing pericardial tamponade. Congestive heart failure is attributed to radiation-induced fibrosis of the myocardium, which ultimately leads to decreased elasticity and extensibility of cardiac walls, thereby reducing the ejection fraction [70]. To learn more about putative mechanisms, the interested reader is referred to some excellent recent reviews [69, 71].

potentially confounding risk factors. For example, occupational studies have to deal with the "healthy worker" effect, and the study of A-bomb survivors has to deal with the "healthy survivor" effect. Both selection effects occur when healthy individuals with lower mortality and morbidity rates are selectively retained at a specific site (work and living area, respectively) where they accumulate higher doses and therefore confound the dose-risk relationship [37]. Other potential confounders in epidemiological studies are lifestyle risk factors for CVD (e.g., smoking, alcohol consumption, obesity, diabetes, hypertension) [35, 55] prognosis of cancer treatment regimens [30], distribution of the dose range, accuracy of dosimetry, duration of follow-up after exposure, and correct assignment of the cause of mortality [62]. For these reasons, the number of people needed to quantify the excess risk of a dose <0.5 Gy is unfeasibly high. In the context of radiation-related cancer, for example, a cohort of 5 million people would be needed to quantify the excess risk of a 10 mGy dose, assuming that the excess risk is in proportion to the dose [7]. Moreover, CVD may occur a long time after exposure to doses below 30 Gy (approx. 10–30 year lag) [30, 72, 73]. As a result, a long follow-up period of time is needed to determine the nature

Selected Endothelial Responses after Ionizing Radiation Exposure

http://dx.doi.org/10.5772/intechopen.72386

373

Despite the fact that epidemiological studies have led to significant insights in radiationrelated CVD risk, there are still many uncertainties that need to be addressed. Does CVD risk occur only above a specific radiation dose? Is the latency of CVD development dependent on the dose? Which are the sensitive targets in the heart and vasculature (e.g., fibroblasts, vascular smooth muscle cells, and endothelial cells)? Does radiation exposure affect CVD incidence or progression or both? Is there a difference between single dose and fractionated and chronic exposure? How does the time interval between two consecutive dose fractionations play a role in the induction of damage? These questions need to be answered to provide a more accurate

Classical epidemiological studies are not adapted to provide answers to these questions. There is, therefore, a clear need for more detailed epidemiological studies that would be capable of addressing potential confounding factors and selection biases that could influence results. Furthermore, there is a particular need for a better understanding of the biological and molecular mechanisms responsible for the association between ionizing radiation and CVD [6]. Hence, a more directed approach is required, such as molecular epidemiology that integrates epidemiology and biology [55]. Radiobiological research is thus essential for understanding the radiation-related CVD risks, both at high and low doses. In other words, accurate risk estimation will be possible only based on comprehensive biological and molecular understanding of what ionizing radiation does to the cardiovascular system. To date, the induction of radiation-related CVD risks is believed to be the

dose risk assessment in order to improve the current radiation protection system.

result of endothelial dysfunction, which will be discussed in the next section [30].

**3. Endothelial cell responses after ionizing radiation exposure**

The endothelium could be a critical target in ionizing radiation-related CVD [74]. The endothelium is a single layer of cells that lines the interior of the vascular system and of the heart and has thus a strategic position between the blood and the surrounding tissues. It is a highly active organ system that is constantly sensing and responding to changes of the extracellular environment to maintain a normal function of the vascular system [75].

and magnitude of risks following individual exposure to lower doses.

#### **2.3. Gaps in the current knowledge of radiation-induced CVD**

Available epidemiological studies have limited statistical power to detect a possible excess risk of CVD following exposure to radiation doses lower than 0.5 Gy. Limited power is due both to the high background level of CVD in studied populations and to the existence of many

**Figure 3.** Longitudinal cut of a normal, healthy blood vessel (left) and of a blood vessel with an atherosclerotic plaque hampering the blood stream (right). Damage to the endothelium is an important trigger of atherosclerosis, itself a main cause of CVD.

potentially confounding risk factors. For example, occupational studies have to deal with the "healthy worker" effect, and the study of A-bomb survivors has to deal with the "healthy survivor" effect. Both selection effects occur when healthy individuals with lower mortality and morbidity rates are selectively retained at a specific site (work and living area, respectively) where they accumulate higher doses and therefore confound the dose-risk relationship [37]. Other potential confounders in epidemiological studies are lifestyle risk factors for CVD (e.g., smoking, alcohol consumption, obesity, diabetes, hypertension) [35, 55] prognosis of cancer treatment regimens [30], distribution of the dose range, accuracy of dosimetry, duration of follow-up after exposure, and correct assignment of the cause of mortality [62]. For these reasons, the number of people needed to quantify the excess risk of a dose <0.5 Gy is unfeasibly high. In the context of radiation-related cancer, for example, a cohort of 5 million people would be needed to quantify the excess risk of a 10 mGy dose, assuming that the excess risk is in proportion to the dose [7]. Moreover, CVD may occur a long time after exposure to doses below 30 Gy (approx. 10–30 year lag) [30, 72, 73]. As a result, a long follow-up period of time is needed to determine the nature and magnitude of risks following individual exposure to lower doses.

As indicated in the epidemiology section, high-dose radiation exposure of the heart and its vessels is associated with a risk of radiation-induced CVD [34, 54, 55]. In this context, coronary artery disease is considered to be the major cardiovascular complication [28, 30, 54]. Two studies provide molecular and cellular mechanisms accounting for increased morbidity and mortality of coronary artery disease following radiation exposure. First, radiation can influence the pathogenesis of age-related atherosclerosis, thereby accelerating the development of atherosclerosis in coronary arteries [28]. Growing atherosclerotic plaques narrow the blood vessel and hamper the blood stream (**Figure 3**). Second, damage to the heart microvasculature can reduce blood flow to the myocardium, causing myocardial ischemia, which promotes acute infarction [30]. Because endothelial activation and dysfunction are major causes of atherosclerosis, much of the current radiobiological research is exploring the molecular and phenotypic effects of ionizing radiation in endothelial cells in the context of radiation-induced CVD [66, 67]. It should be noted, however, that there are also other clinical manifestations of radiation-related CVD, such as pericarditis, congestive heart failure, and heart fibrosis [30, 68, 69]. Radiation-induced pericarditis is caused by damage to the cardiac microvascular network in combination with fibrosis of cardiac venous and lymphatic channels. This ultimately leads to accumulation of a fibrin-rich exudate in the pericardium, causing pericardial tamponade. Congestive heart failure is attributed to radiation-induced fibrosis of the myocardium, which ultimately leads to decreased elasticity and extensibility of cardiac walls, thereby reducing the ejection fraction [70]. To learn more about putative mechanisms, the interested reader is referred to some excellent recent reviews [69, 71].

Available epidemiological studies have limited statistical power to detect a possible excess risk of CVD following exposure to radiation doses lower than 0.5 Gy. Limited power is due both to the high background level of CVD in studied populations and to the existence of many

**Figure 3.** Longitudinal cut of a normal, healthy blood vessel (left) and of a blood vessel with an atherosclerotic plaque hampering the blood stream (right). Damage to the endothelium is an important trigger of atherosclerosis, itself a main

**2.3. Gaps in the current knowledge of radiation-induced CVD**

372 Endothelial Dysfunction - Old Concepts and New Challenges

cause of CVD.

Despite the fact that epidemiological studies have led to significant insights in radiationrelated CVD risk, there are still many uncertainties that need to be addressed. Does CVD risk occur only above a specific radiation dose? Is the latency of CVD development dependent on the dose? Which are the sensitive targets in the heart and vasculature (e.g., fibroblasts, vascular smooth muscle cells, and endothelial cells)? Does radiation exposure affect CVD incidence or progression or both? Is there a difference between single dose and fractionated and chronic exposure? How does the time interval between two consecutive dose fractionations play a role in the induction of damage? These questions need to be answered to provide a more accurate dose risk assessment in order to improve the current radiation protection system.

Classical epidemiological studies are not adapted to provide answers to these questions. There is, therefore, a clear need for more detailed epidemiological studies that would be capable of addressing potential confounding factors and selection biases that could influence results. Furthermore, there is a particular need for a better understanding of the biological and molecular mechanisms responsible for the association between ionizing radiation and CVD [6]. Hence, a more directed approach is required, such as molecular epidemiology that integrates epidemiology and biology [55]. Radiobiological research is thus essential for understanding the radiation-related CVD risks, both at high and low doses. In other words, accurate risk estimation will be possible only based on comprehensive biological and molecular understanding of what ionizing radiation does to the cardiovascular system. To date, the induction of radiation-related CVD risks is believed to be the result of endothelial dysfunction, which will be discussed in the next section [30].
