A major cause of morbidity and mortality in patients

A major cause of morbidity and mortality in patients that are under therapeutic chest irradiation is radiation- induces cardiovascular pathology. There is a broad range of clinical demonstration that is perhaps linked with dose, technique and volume of irradiation. It is assumed that prevention is the best way to manage and reduce the radiation induced cardiovascular disease and there are various literature reports that support this idea. It is also considered that the occurrence of cardiovascular disease in patients is mainly affected by breast cancer and/or Hodgkin’s lymphoma. Some researchers (Hooning, Botma, Aleman et al., 2007), (Aleman et al., 2003) (Swerdlow, Higgins, Smith et al., 2007) discuss the domestic prevention in terms of therapeutic procedures and doses such as IMRT, with particular linkage to the affect on cardio toxicity of parameters as MHD, MLD and NTCP.    Cancer and cardiovascular disease are the two foremost causes of mortality worldwide. With the help of improving cancer treatment, many patients have survived cancer, some of whom now suffer with cardiovascular effects of the radiation therapy they received. To ensure that no fatal harm is given to the patient through radiation, long-term follow up checkups are essential, as heart complications seem to begin years after the completion of any radiation therapy. This paper discusses the cardiovascular effects of radiation therapy.

Radiation therapy is pain itself. Many low-dose palliative treatments (e.g. radiotherapy for bone metastases) cause minimal or no side effects, although short-term pain flare up can be experienced in the coming days treatment due to nerve compression edema in the treated area. Treatment to higher doses causes many side effects during treatment (acute side effects), in the months or years after treatment (long-term side effects), or after re-treatment (cumulative side effects). The nature, severity and duration of side effects depends on the organs that receive the radiation, the treatment itself (type of radiation, dose, fractionation, concurrent chemotherapy), and patient. Heart disease is a late complication of radiation to the mediastinum. A research conducted by Heidenreich, Schnittger, Strauss et al. (2007) a group of 157 patients who received primary treatment with radiation to the mediastinum, 8.3% died of heart disease, which is 5 times more than expected for this age group. The risk of heart disease is associated with high doses of radiation and radiation fields greater.

No one has ever been able to identify the precise mechanism of how radiation induces or persuades atherosclerosis in patients. There are various acute effects which include the damage of endothelial, infiltration of inflammatory cells and lipid and activation of lysosomal, have been observed. However, a primary basic mechanism behind the occurrence of cardiovascular disease due to radiation is explained to be due to the dysfunction of endothelial. Besides, there are certain risk factors including smoking and hyperlipidemia appears to act as a catalyst. Fibrotic changes in the coronary arteries can be caused by radiation; however, an increased in the degree of atherosclerosis is caused by cholesterol feeding of the animals, especially in rabbits. It is suggested through these findings that a joint effect of irradiation and other risk factors is important for the production of significant radiation-induced atherosclerosis.

Most side effects are expected and predictable. The radiation side effects are generally limited to the region of the patient’s body that is treated. One of the aims of modern radiotherapy is to reduce side effects to a minimum and to help the patient understand and cope with the side effects are inevitable. New research suggests that inflammation induced by radiation changes in gene expression in the arteries of the heart, after treatment with radiation, may be the cause of the increased risk of cardiovascular disease in cancer survivors. The problem is growing as more and more people survive the disease, after receiving radiation as a therapy. Epidemiological studies have shown that the radiation increases the risk of cardiovascular disease in the same body part. For example, the patient is more likely to have a myocardial infarction after treatment for left breast cancer, or stroke can occur after treatment of tumors in the head. Scientists know very little, however, about the biological causes of these serious side effects that often only appear many years after treatment (Swerdlow, Higgins, Smith et al., 2007).

Figure 1: Doppler echocardiogram of the aortic valve (Virmani, Farb, Carter and Jonesa, 1999)

Figure 1 is of a patient who received therapy for Hodgkin’s disease in 1976. The 46 year old female’s heart showed some degree of regurgitation was noted in all 4 valves. The evaluation of the grafts that were performed after cancer researcher Martin Halle (Hooning, Botma, Aleman et al., 2007) was able to study the long-term effects, radiation in human blood vessels. Such grafting involves the transplantation of skin tissue, muscle or bone of a body part of a patient to reconstruct defects occurring after removal of a tumor. By collecting specimen’s branches, the carotid artery grafts previously irradiated and un-irradiated artery, researchers were able to compare the overall difference in gene expression between the two types of grafts from the same patient simultaneously. They found that the irradiated arteries showed signs of chronic inflammation and increased the activity of nuclear factor-kappa B transcription factor (NF-kappa B) known to play a key role in the development of atherosclerosis. The increased expression of inflammatory genes was visible for several years after irradiation as to why cancer patients can suffer from cardiovascular disease for many years after radiotherapy.

Cardiovascular disease is the leading cause of death and a leading cause of disability in developed countries, as reported in the paper and also by the World Health Organization (Ng, Bernardo, Weller et al., 2002). For some time, scientists have understood how high-dose radiotherapy (RT) causes inflammation in the heart and large arteries and how this translates into increased levels of cardiovascular disease observed in many groups of patients receiving RT (high-dose radiation therapy). However, in recent years, studies have also shown that may have cardiovascular risks associated with much lower doses of radiation received by fractional groups such as nuclear workers, but it is unclear what biological mechanisms are responsible.

Dr. Mark Little (Ng, Bernardo, Weller et al., 2002), has explored a novel mechanism that suggests that radiation kills monocytes (a type of white blood cell) in the arterial wall, which would otherwise bind to proteins monocyte chemo-attractant 1 (MCP-1). Higher levels cause inflammation of MCP-1, which leads to cardiovascular disease. Besides being consistent with what is seen in nuclear workers, changes in MCP-1 caused by cholesterol predict that the model is consistent with experimental and epidemiologic data. If the mechanism is valid implies that the risks of exposures to low doses of radiation (e.g., medical and dental X-rays), which until now have been assumed to result only from cancer, may have been underestimated (Ng, Bernardo, Weller et al., 2002).

Figure 2: Porcine coronary arteries (Virmani, Farb, Carter and Jonesa, 1999)

Figure 1: Doppler echocardiogram of the aortic valve (Virmani, Farb, Carter and Jonesa, 1999)

In figure 2, part A shows results in uneven initial exterior with stent struts (*) enclosed by fibrin and fascinated erythrocytes; soft muscle cells are not apparent and in part B, Directs to the growth of a more adult, thicker neointima containing profuse smooth muscle cells and matrix. Attentive extravasated erythrocytes (gray color) enclose stent struts. The initiation of atherosclerosis was previously associated with the lipid accumulation with the walls of the arteries, but now it is accepted that inflammation plays an important role in the starting up and progression of the disease. In the animal model, irradiation speeded the development of macrophage-rich inflammatory atherosclerotic lesions prone to intraplaque hemorrhage as well as affecting the atherogenic effects of high fat diet (Aleman et al., 2003). It is assumed that short lived changes in the conditions of oxidative stress are promoted by radiation in the walls of the arteries. Moreover, atherogenic lipoproteins are eminent in reaction to the high fat diet. These two factors must be present during the radiation to initiate the disease process. Furthermore, a mechanism of radiation that induces dysfunction of endothelial is through the production of oxygen species which are reactive. Major increase in the superoxide as well as peroxide has been observed by Hoppe (1997) in his research.

In 1999 Marie Overgaard et al. published results in morbidity and mortality of two randomized trials with 3083 patients at high risk (Bleyer, 1990). Half of them received postoperative radiation therapy to the chest wall and lymph node chains. The wall and the ipsilateral internal mammary nodes were irradiated with electrons. The energy thereof is calculated by measuring the wall thickness by ultrasound. Supra clavicular lymph, axillaries and subclavian irradiated with a beam of photons, considering heart and lung protections. According to radiobiological studies, the toxicity of heart tissue damage should the vascular-connective (endothelial cells, smooth muscle and fibroblasts). Radiation damage leads to degeneration of myocytes and developed fibrotic lesions. During the last decades there has been a better understanding of the biological changes caused by irradiation or histopathological not only functional but also biochemical and molecular. The heart is a late responding tissue with value a / b <5 Gy. In contrast to other tissues late responders, heart after receiving the maximum tolerated dose absorbed, is not able to recover long time (Fuster and Voûte, 2005).



Figure 3: Histologic section of the left circumflex coronary artery from a 67-year-old patient who received radiation therapy for carcinoma of the lung 7 years prior to sudden death (Virmani, Farb, Carter and Jonesa, 1999).

There is evidence that in the mediastinum irradiation can induce or accelerate the coronary arteriosclerosis, although the mechanism has not been fully clarified. As proof of this, young people who received radiation to the mediastinum and subsequently suffered myocardial infarction, atherosclerosis was not found outside the irradiated volume. Fuller et al. (1992) and Rutqvist et al. (1990) have shown that different techniques left breast irradiation influence the dose delivered to the heart. This was proven in one of the trials conducted in Stockholm, which included women with early stage breast cancer treated with conservative surgery and breast irradiation. The aim of the study was to investigate the incidence of myocardial infarction. Reviewed the CT simulation of 100 patients with breast cancer and found that the left heart was very previously located in the mediastinum in 6% of patients. This finding suggests that this standard simulation techniques unfavorable anatomy would not be detected by the inability to see the heart without CT. The Boston Group investigated the relationship between breathing movements and the amount of heart involved during irradiation of the left breast with two tangential fields opposite and parallel. Showed variability in the amount of heart irradiated during inspiration being less profound and sustained. The conclusion JCRT in this and other studies was that irradiation of breast volume with modern radiotherapy techniques including three-dimensional virtual simulation and planning, is not associated with increased risk of cardiac mortality up to 12 years of follow up, the result was the same for right and left breast  (Lu, Cash, Chen et al., 2000).

According to the research by (Yusuf, Sami and Daher, 2010) asymptomatic disease is also common in patients with previous radiation. New perfusion defects occurred in 50% to 63% of women 6 to 24 months after RT. Marks et al. demonstrate 27%, 29%, 38%, and 42% incidence of myocardial perfusion abnormalities in asymptomatic patients with breast cancer. The occurrence of perfusion deficiency was powerfully linked with the volume of left ventricle (LV) in the RT field occurring in 25% of patients with 1% to 5% of the LV within the tangent fields, and in 55% of patients with more than 5% of the LV within the field. The clinical implication of these perfusion deficiencies is unidentified. Though, they emerge to be linked with irregularities in wall movement and occurrence of chest pain. An insignificant change in ejection fraction is apparent only in patients with relatively large fractions of the LV affected by perfusion defects. In a patient suffering from distal esophageal cancer, RT is connected with an elevated occurrence of lower left ventricular ischemia, as identified by gated myocardial perfusion descriptions (GMPIs). The majority of perfusion defects are covered within an isodose line ≥45 Gy in the RT plan.  Moreover, most patients have mild degree of ischemia.

A wall motion abnormality is seen in some patients suffering from radiation induced cardiovascular disease; such result is likely due to the existence of only mild scale of ischemia. In the deficiency of risk factors, the role of avoidance therapy like use of antiplatelets, ACE inhibitors, and lipid lowering agents is unclear (Lu, Cash, Chen et al., 2000). Lately CT scan of the coronary artery has been recognized as a helpful tool in discovering RICAD in asymptomatic patients. Earlier, radiation therapy signifies that the preponderance have mild myocardial perfusion defects. In patients with good long-term prognosis, the finding of the ischemia due to the RT may be important as this is a reversible and treatable stage of RICAD, and its hesitant progression may reduce the occurrence of future cardiovascular events. Technological development has caused increasing exposure of humans to electromagnetic radiation of various kinds. The effects of ionizing radiation called on life are quite well known and methods to prevent these effects have been regulated in most countries. However, the health effects of radiation on cardiovascular diseases, have been less studied and therefore, there is insufficient regulation on measures to reduce or avoid potential adverse health effects.


Berthe M.P. Aleman et al. (2003), Long-term cause-specific mortality of patients treated for Hodgkin’s disease, Journal of Clinical Oncology, vol. 21(18), pp. 3431–3439 [http://jco.ascopubs.org/content/21/18/3431.full.pdf]

  1. ArchieBleyer, (1990), The impact of childhood cancer on the United States and the world, Ca: A Cancer Journal for Clinicians, vol. 40 (6), pp. 355–367

Fuster, V. and Voûte, J. (2005), MDGs: chronic diseases are not on the agenda, The Lancet, vol. 366(9496), pp. 1512–1514.

Fuller SA, Haybittle JL, Smith REA, et al (1992), Cardiac doses in post-operative breast irradiation. Radiother Oncol. Vol. 25, pp. 19-24

Hooning, M. J., Botma, A., Aleman, B. M. P. et al. (2007), Long-term risk of cardiovascular disease in 10-year survivors of breast cancer, Journal of the National Cancer Institute, vol. 99 (5), pp. 365–375

Heidenreich, P. A., Schnittger, I., Strauss, H. W. et al. (2007), Screening for coronary artery disease after mediastinal irradiation for Hodgkin’s disease, Journal of Clinical Oncology, Vol. 25 (1), pp. 43–49

Hoppe, R. T. (1997), Hodgkin’s disease: complications of therapy and excess mortality, Annals of Oncology, Vol. 8 (1), pp. 115–118

Lu H, Cash E, Chen MH, Chin L, Manning Warren, Harris J, Bornstein B (2000), Reduction of cardiac volume in left-breast treatment fields by respiratory maneuvers: A CT study. Int J Radiat Oncol. Biol Phys, Vol. 47, pp. 895-904

Ng, A.K., Bernardo, M.P., Weller, E. et al. (2002), Long-term survival and competing causes of death in patients with early-stage Hodgkin’s disease treated at age 50 or younger, Journal of Clinical Oncology, vol. 20 (8), pp. 2101–2108

Rutqvist LE, Johansson H, (1990), Mortality by laterality of the primary tumours among 55,000 breast cancer patients from the Swedish cancer registry. Br J Cancer 61: 866-868.

Renu Virmani , Andrew Farb, Andrew J Carter, Russ M Jonesa (1999), Pathology of radiation-induced coronary artery disease in human and pig, Cardiovascular Radiation Medicine, Vol. 1(1), pp. 98-101

Syed Wamique Yusuf, Shehzad Sami, and Iyad N. Daher (2010), Radiation-Induced Heart Disease: A Clinical Update, Cardiology Research and Practice, Volume 2011 (2011), Article ID 317659, 9 pages

Swerdlow, A. J., Higgins, C. D., Smith, P. et al. (2007), Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study, Journal of the National Cancer Institute, vol. 99(3), pp. 206–214