Development Of Radiation-induced Heart Disease Research Articles

РАДИАЦИОННО-ИНДУЦИРОВАННАЯ БОЛЕЗНЬ СЕРДЦА: ПРИЧИНЫ, ПРОЯВЛЕНИЯ, ПРОФИЛАКТИКА

The article discusses the causes of the development of radiation-induced heart disease - one of the significant complications of chest radiation therapy. Treating cancer with this method triggers the mechanism of pathological changes in the heart. There are a number of risk factors contributing to this complication in patients. The most common clinical forms of radiation-induced heart disease are identified, as well as a characteristic of their signs. The timing of the appearance of these signs for each form may be different, in addition, they vary depending on the reason for the use of radiation therapy. The possibilities of diagnosing selected conditions are indicated, which oncologists and doctors of other specialties should actively apply in the tactics of managing patients who have undergone oncological diseases of the mammary glands or chest organs. These diagnostic methods are not different from the main methods of diagnosing cardiac diseases, they are affordable and safe. The article also provides methods for the primary and secondary prevention of radiation-induced heart disease, which begin with the choice of a method of treatment for an oncological patient. Now there are many radiotherapy options that reduce the dose and area of radiation, which can minimize the risks of deterioration in the quality of life and prognosis of the patient. The next important principle is the correction of lifestyle and modifiable cardiovascular risk factors. Also indicated are variants of drugs used in cardiac practice, with the help of which, possibly, in the future, the prevention of radiation-induced heart disease will be carried out, but so far they are at the stage of clinical trials.

Effects of Whole and Partial Heart Irradiation on Collagen, Mast Cells, and Toll-like Receptor 4 in the Mouse Heart.

In radiation therapy of tumors in the chest, such as in lung or esophageal cancer, part of the heart may be situated in the radiation field. This can lead to the development of radiation-induced heart disease. The mechanisms by which radiation causes long-term injury to the heart are not fully understood, but investigations in pre-clinical research models can contribute to mechanistic insights. Recent developments in X-ray technology have enabled partial heart irradiation in mouse models. In this study, adult male and female C57BL/6J mice were exposed to whole heart (a single dose of 8 or 16 Gy) and partial heart irradiation (16 Gy to 40% of the heart). Plasma samples were collected at 5 days and 2 weeks after the irradiation for metabolomics analysis, and the cardiac collagen deposition, mast cell numbers, and left ventricular expression of Toll-like receptor 4 (TLR4) were examined in the irradiated and unirradiated parts of the heart at 6 months after the irradiation. Small differences were found in the plasma metabolite profiles between the groups. However, the collagen deposition did not differ between the irradiated and unirradiated parts of the heart, and radiation did not upregulate the mast cell numbers in either part of the heart. Lastly, an increase in the expression of TLR4 was seen only after a single dose of 8 Gy to the whole heart. These results suggest that adverse tissue remodeling was not different between the irradiated and unirradiated portions of the mouse heart. While there were no clear differences between male and female animals, additional work in larger cohorts may be required to confirm this result, and to test the inhibition of TLR4 as an intervention strategy in radiation-induced heart disease.

Preclinical models of radiation-induced cardiac toxicity: Potential mechanisms and biomarkers.

Radiation therapy (RT) is an important modality in cancer treatment with >50% of cancer patients undergoing RT for curative or palliative intent. In patients with breast, lung, and esophageal cancer, as well as mediastinal malignancies, incidental RT dose to heart or vascular structures has been linked to the development of Radiation-Induced Heart Disease (RIHD) which manifests as ischemic heart disease, cardiomyopathy, cardiac dysfunction, and heart failure. Despite the remarkable progress in the delivery of radiotherapy treatment, off-target cardiac toxicities are unavoidable. One of the best-studied pathological consequences of incidental exposure of the heart to RT is collagen deposition and fibrosis, leading to the development of radiation-induced myocardial fibrosis (RIMF). However, the pathogenesis of RIMF is still largely unknown. Moreover, there are no available clinical approaches to reverse RIMF once it occurs and it continues to impair the quality of life of long-term cancer survivors. Hence, there is an increasing need for more clinically relevant preclinical models to elucidate the molecular and cellular mechanisms involved in the development of RIMF. This review offers an insight into the existing preclinical models to study RIHD and the suggested mechanisms of RIMF, as well as available multi-modality treatments and outcomes. Moreover, we summarize the valuable detection methods of RIHD/RIMF, and the clinical use of sensitive radiographic and circulating biomarkers.

An overview of radiation-induced heart disease.

Radiation therapy (RT) has dramatically improved cancer survival, leading to several inevitable complications. Unintentional irradiation of the heart can lead to radiation-induced heart disease (RIHD), including cardiomyopathy, pericarditis, coronary artery disease, valvular heart disease, and conduction system abnormalities. Furthermore, the development of RIHD is aggravated with the addition of chemotherapy. The screening, diagnosis, and follow-up for RIHD in patients who have undergone RT are described by the consensus guidelines from the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE). There is compelling evidence that chest RT can increase the risk of heart disease. Although the prevalence and severity of RIHD are likely to be reduced with modern RT techniques, the incidence of RIHD is expected to rise in cancer survivors who have been treated with old RT regimens. However, there remains a gap between guidelines and clinical practice. Currently, therapeutic modalities followed in the treatment of RIHD are similar to the non-irradiated population. Preventive measures mainly reduce the radiation dose and radiation volume of the heart. There is no concrete evidence to endorse the preventive role of statins, angiotensin-converting enzyme inhibitors, and antioxidants. This review summarizes the current evidence of RIHD subtypes and risk factors and suggests screening regimens, diagnosis, treatment, and preventive approaches.

No changes in myocardial perfusion following radiation therapy of left-sided breast cancer: A positron emission tomography study

BackgroundAdjuvant radiation therapy (RT) for breast cancer has improved overall survival. However, incidental exposure of the heart has been linked to development of radiation-induced heart disease. The aim of this study was, in a cohort of asymptomatic post-irradiation breast cancer patients, to investigate changes in myocardial blood flow (MBF) and presence of perfusion defects in myocardial perfusion positron-emission-tomography (PET) in the irradiated myocardium. Methods and ResultsTwenty patients treated with RT for left-sided breast cancer underwent 13N-ammonia myocardial perfusion PET 7(± 2) years after breath adapted RT to a total dose of 48 Gy given in 24 fractions. No differences in rest or stress MBF were noted between the irradiated and non-irradiated myocardium (1.29 (± 0.29) vs 1.33 (± 0.29) mL/g/min, ns; 2.74 (± 0.59) vs 2.78 (± 0.66) mL/g/min, ns, respectively). One patient demonstrated a myocardial perfusion defect localized in the irradiated anterior wall myocardium. ConclusionAlthough limited by a small sample size, early signs of cardiac injury detected by NH3 myocardial perfusion PET was at least not frequent in our cohort of patients treated with a modern RT technique for left-sided breast cancer, even 7 years after treatment. The findings however, may not rule out subsequent development of myocardial injury.

Pituitary Adenylate Cyclase-Activating Polypeptide Ameliorates Radiation-Induced Cardiac Injury

Radiation-induced heart disease (RIHD) is a common sequelae of thoracic irradiation. Oxidative stress is associated with the development of RIHD. Studies have shown that pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) represents the multipotent properties of cytoprotective effect on its anti-inflammatory, anti-apoptotic and antioxidant activities. If PACAP38 plays a role in attenuating RIHD remains investigation. In the present study, the culture of rat H9C2 cardiomyocytes was subjected to irradiation (IR) in vitro. Cardiac injury was performed to expose murine heart for IR. H9C2 cells and C57 mice were pre-treated with PACAP38 at different doses prior to radiation exposure. The effects of PACAP38 was evaluated by cell viability assay (CCK8), plate clone formation assay, cell cycles and apoptosis of flow cytometry. Apoptosis-related proteins, cell cycle-associated proteins and NRF2/HO-1 were determined by qRT-PCR and Western blot. The transient knockdown of NRF2 signaling by siRNA was also examined to explore the possible abortion of cytoprotection of PACAP38. H-E, Masson and TUNEL staining were performed in vivo in mouse model of IR. Cell viability was enhanced for 15-20% higher in H9C2 cardiomyocytes treated with PACAP38 (10-7M)+IR (12Gy) than in cardiomyocytes exposed to radiation (12Gy) alone (PACAP38+IR vs. IR, P<0.01). 10-7M PACAP38 increased colony-forming efficiency by 23%, 41% and 3 fold at IR doses of 2Gy, 4Gy and 8Gy, respectively. PACAP38 suppressed myocardial apoptosis and G2/M arrest through blunting the radiation-induced down-regulation of Bcl-2, CyclinB1 and CDK1, and inhibiting the up-regulation of Bax. IR resulted in activating of NRF2 and HO-1 expressions were further enhanced by PACAP38 at 10-7M concentration in H9C2 cells. The protective effect of PACAP38 was partially blocked by Nrf2 siRNA silencing (PACAP38+IR vs. PACAP38+IR+SiNrf2, P<0.05). Moreover, treatment with PACAP38 (10μg, i.p.) protected mice from histological damage by significantly inhibition of myocardial apoptosis. Our results indicate that PACAP38 has the potential to effectively protect against acute radiation-induced cardiac injury and its cardioprotective effect involves upregulation of Nrf2/HO-1-dependent signaling activation.

Selective Heart Irradiation Induces Cardiac Overexpression of the Pro-hypertrophic miR-212.

Background: A deleterious, late-onset side effect of thoracic radiotherapy is the development of radiation-induced heart disease (RIHD). It covers a spectrum of cardiac pathology including also heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction. MicroRNA-212 (miR-212) is a crucial regulator of pathologic LVH via FOXO3-mediated pathways in pressure-overload-induced heart failure. We aimed to investigate whether miR-212 and its selected hypertrophy-associated targets play a role in the development of RIHD.Methods: RIHD was induced by selective heart irradiation (50 Gy) in a clinically relevant rat model. One, three, and nineteen weeks after selective heart irradiation, transthoracic echocardiography was performed to monitor cardiac morphology and function. Cardiomyocyte hypertrophy and fibrosis were assessed by histology at week 19. qRT-PCR was performed to measure the gene expression changes of miR-212 and forkhead box O3 (FOXO3) in all follow-up time points. The cardiac transcript level of other selected hypertrophy-associated targets of miR-212 including extracellular signal-regulated kinase 2 (ERK2), myocyte enhancer factor 2a (MEF2a), AMP-activated protein kinase, (AMPK), heat shock protein 40 (HSP40), sirtuin 1, (SIRT1), calcineurin A-alpha and phosphatase and tensin homolog (PTEN) were also measured at week 19. Cardiac expression of FOXO3 and phospho-FOXO3 were investigated at the protein level by Western blot at week 19.Results: In RIHD, diastolic dysfunction was present at every time point. Septal hypertrophy developed at week 3 and a marked LVH with interstitial fibrosis developed at week 19 in the irradiated hearts. In RIHD, cardiac miR-212 was overexpressed at week 3 and 19, and FOXO3 was repressed at the mRNA level only at week 19. In contrast, the total FOXO3 protein level failed to decrease in response to heart irradiation at week 19. Other selected hypertrophy-associated target genes failed to change at the mRNA level in RIHD at week 19.Conclusions: LVH in RIHD was associated with cardiac overexpression of miR-212. However, miR-212 seems to play a role in the development of LVH via FOXO3-independent mechanisms in RIHD. As a central regulator of pathologic remodeling, miR-212 might become a novel target for RIHD-induced LVH and heart failure.

Cardiovascular complications of radiation exposure.

The cardiovascular sequelae of radiation exposure are an important cause of morbidity and mortality following radiation therapy for cancer, as well as after exposure to radiation after atomic bombs or nuclear accidents. In the United States, most of the data on radiation-induced heart disease (RIHD) come from patients treated with radiation therapy for Hodgkin disease and breast cancer. Additionally, people exposed to radiation from the atomic bombs in Hiroshima and Nagasaki, Japan, and the Chernobyl, Ukraine, nuclear accident have an increased risk of cardiovascular disease. The total dose of radiation, as well as the fractionation of the dose, plays an important role in the development of RIHD. All parts of the heart are affected, including the pericardium, vasculature, myocardium, valves, and conduction system. The mechanism of injury is complex, but one major mechanism is injury to endothelium in both the microvasculature and coronary arteries. This likely also contributes to damage and fibrosis within the myocardium. Additionally, various inflammatory and profibrotic cytokines contribute to injury. Diagnosis and treatment are not significantly different from those for conventional cardiovascular disease; however, screening for heart disease and lifelong cardiology follow-up is essential in patients with past radiation exposure.

Radiation-Induced Alterations in Mitochondria of the Rat Heart

Radiation therapy for the treatment of thoracic cancers may be associated with radiation-induced heart disease (RIHD), especially in long-term cancer survivors. Mechanisms by which radiation causes heart disease are largely unknown. To identify potential long-term contributions of mitochondria in the development of radiation-induced heart disease, we examined the time course of effects of irradiation on cardiac mitochondria. In this study, Sprague-Dawley male rats received image-guided local X irradiation of the heart with a single dose ranging from 3-21 Gy. Two weeks after irradiation, left ventricular mitochondria were isolated to assess the dose-dependency of the mitochondrial permeability transition pore (mPTP) opening in a mitochondrial swelling assay. At time points from 6 h to 9 months after a cardiac dose of 21 Gy, the following analyses were performed: left ventricular Bax and Bcl-2 protein levels; apoptosis; mitochondrial inner membrane potential and mPTP opening; mitochondrial mass and expression of mitophagy mediators Parkin and PTEN induced putative kinase-1 (PINK-1); mitochondrial respiration and protein levels of succinate dehydrogenase A (SDHA); and the 70 kDa subunit of complex II. Local heart irradiation caused a prolonged increase in Bax/Bcl-2 ratio and induced apoptosis between 6 h and 2 weeks. The mitochondrial membrane potential was reduced until 2 weeks, and the calcium-induced mPTP opening was increased from 6 h up to 9 months. An increased mitochondrial mass together with unaltered levels of Parkin suggested that mitophagy did not occur. Lastly, we detected a significant decrease in succinate-driven state 2 respiration in isolated mitochondria from 2 weeks up to 9 months after irradiation, coinciding with reduced mitochondrial levels of succinate dehydrogenase A. Our results suggest that local heart irradiation induces long-term changes in cardiac mitochondrial membrane functions, levels of SDH and state 2 respiration. At any time after exposure to radiation, cardiac mitochondria are more prone to mPTP opening. Future studies will determine whether this makes the heart more susceptible to secondary stressors such as calcium overload or ischemia/reperfusion.

Studies on Pentoxifylline and Tocopherol Combination for Radiation-Induced Heart Disease in Rats

To investigate whether the application of pentoxifylline (PTX) and tocopherol l (Vit. E) could modify the development of radiation-induced heart disease and downregulate the expression of transforming growth factor (TGF)-beta1mRNA in rats. A total of 120 Sprague-Dawley rats were separated into four groups: control group, irradiated group, experimental group 1, and experiment group 2. Supplementation was started 3 days before irradiation; in experimental group 1, injection of PTX (15 mg/kg/d) and Vit. E (5.5 mg/kg/d) continued till the 12th week postirradiation, whereas in experimental group 2 it was continued until the 24th week postirradiation. All rats were administrated a single dose of 20 Gy irradiation to the heart except the control group. Histopathologic evaluation was performed at various time points (Days 1, 2, 4, 8, and 12 and 24th week) up to 24 weeks after irradiation. Changes of levels of TGF-beta1 mRNA expression were also investigated at the same time points using competitive polymerase chain reaction. Compared with the irradiated group, levels of TGF-beta1 mRNA of the rat hearts were relatively low in the two experimental groups on the 12th week postirradiation. In experimental group 1, there was a rebound expression of TGF-beta1 mRNA on the 24th week postirradiation, whereas that of the experimental group 2 remained low (p < 0.05). The proportions of collagen fibers of the two experimental groups were lower than that of irradiated group (p < 0.05). A rebound could be observed in the experimental group 1. PTX and Vit. E downregulated the expression of TGF-beta1 mRNA. The irradiated rat hearts showed a marked pathologic response to the drugs. The withdrawal of drugs in the 12th week postirradiation could cause rebound effects of the development of fibrosis.

Interactions between mast cells and the endothelin system in radiation‐induced heart disease

Objectives Mast cells may influence the development of radiation-induced heart disease (RIHD), an important sequela after thoracic radiotherapy. Moreover, mast cells regulate levels of endothelin 1 (ET-1), which plays a role in cardiovascular remodeling via its receptors, ETA and ETB. This study used a mast cell-deficient rat model to investigate interactions between mast cells and the cardiac endothelin system in RIHD. Methods Mast cell-deficient (Ws/Ws) and mast cell-competent (+/+) rats were exposed to 18 Gy localized irradiation of the heart. Cardiac functional changes were assessed using echocardiography and Langendorff isolated heart preparation 6 months after irradiation. Localization and mRNA levels of ET-1, ETA and ETB were examined at 1 week and 3 months. Results Irradiated hearts from mast cell-competent rats exhibited more severe myocardial degeneration, but less severe diastolic dysfunction than irradiated hearts from mast cell-deficient rats. Post-radiation ET-1 mRNA levels were strikingly increased in mast cell-competent, but not in mast cell-deficient hearts. Cardiac mast cells exhibited prominent ETA and ETB immunoreactivity. Conclusions These data suggest that crosstalk between mast cells and the endothelin system may be important during the development of RIHD and point to ET-1 and/or its receptors as possible therapeutic targets to reduce RIHD. Research support National Institutes of Health and the American Heart Association.

Endothelial Alkaline Phosphatase Activity Loss as an Early Stage in the Development of Radiation-Induced Heart Disease in Rats

Alkaline phosphatase activity of capillary endothelial cells in the heart of Wistar and Sprague-Dawley rats was studied sequentially after single doses of 10, 15, 20, or 25 Gy. Following irradiation capillary density and alkaline phosphatase activity were focally lost before myocardial degeneration or clinical symptoms of heart disease developed. Recovery from both changes took place after doses of 10 or 15 Gy. The decrease in capillary density and enzyme activity showed the same strain difference in latency times and in the extent of the lesions as previously described for pathological and clinical signs of heart disease.