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Objective:To investigate the regulatory effect of miR-26a in radiation-induced heart disease (RIHD) mice.Methods:C57/BL6 mice were used to establish RIHD models. The cardiac function, fibrosis, the expression levels of collagen 1 (COL1) and connective tissue growth factor (CTGF), and miR-26a were detected in RIHD mice. Whether CTGF was the target gene of miR-26a was verified by dual luciferase kit. Moreover, cardiac fibroblasts were transfected with miR-26a up and miR-26a down lentivirus vectors to construct the miR-26a overexpression and underexpression cell models. The expression of CTGF, proliferation, and apoptosis of cardiac fibroblasts were detected.Results:In the RIHD mice, heart function was decreased, myocardial fibrosis was remodeled, the expression levels of COL1 and CTGF were up-regulated, and the expression level of miR-26a was down-regulated. Dual luciferase reporter assay confirmed that CTGF was the target gene regulated by miR-26a. Overexpression of miR-26a could inhibit the expression of CTGF, suppress the proliferation of cardiac fibroblasts, promote cell apoptosis and secrete collagen. Underexpression of miR-26a yielded the opposite results.Conclusion:MiR-26a affects the function of cardiac fibroblasts by targeting CTGF and probably mediates the process of radiation-induced myocardial fibrosis, which may become a new regulatory target of RIHD.
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In recent years, radiotherapy has been widely applied in tumor patients. The short-term and long-term impact on the cardiovascular system has captivated increasing attention from radiologist and cardiologist. Along with higher radiation dose and longer follow-up, the incidence rate of coronary artery disease tends to significantly elevate, especially in patients with breast cancer and lung cancer. With the advancement of radiotherapy technologies, different tumors, different radiation doses and different modes of radiation delivery exert different effects on coronary artery. There are still some disputes about how to prevent, diagnose, evaluate, and treat the high-risk population of coronary artery diseases after radiotherapy. How to optimize the treatment strategy before and after radiotherapy to reduce the incidence of short-term and long-term coronary artery diseases in cancer patients needs further clinical research.
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@#It has been recognized that long-term exposure of the heart to high-dose ionizing radiation can result in cardiac injury. Nevertheless, recent epidemiological, experimental, and clinical studies have demonstrated that exposure to low-dose ionizing radiation may also cause cardiovascular injury via various mechanisms. This article reviews the cardiac injury and potential cardiovascular risk caused by ionizing radiation, summarizes the currently available non-invasive approaches used for detecting radiation-induced cardiac injury, and proposes interventions to prevent and alleviate it, with the hope of providing a reference for early identification and interventions for radiation-induced cardiac injury.
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Resumen La radioterapia representa una herramienta terapéutica de gran utilidad en el tratamiento de varios tipos de cáncer. Cuando se emplea a lesiones en tórax existe el riesgo de aplicar determinada radiación en el corazón y consecuentemente presentar complicaciones cardíacas. Los efectos adversos se pueden observar en los distintos componentes del corazón y las manifestaciones pueden apreciarse principalmente a largo plazo. Mediante una evaluación integral del riesgo cardiovascular, la identificación de las terapias concomitantes con potencial cardiotóxico, la aplicación de técnicas de radioterapia con función protectora del corazón y el control con estudios cardiológicos se intenta optimizar el desenlace oncológico y cardiovascular de los pacientes. En aquellos pacientes que se presenten con complicaciones cardíacas, existen varias opciones terapéuticas tanto quirúrgicas como percutáneas, que implican un desafío dado la complejidad de los casos. Finalmente, existen distintas consideraciones de manejo para los pacientes con dispositivos electrónicos cardíacos implantables. Estrategia de búsqueda: Se realizó una búsqueda en Pubmed de artículos bajo el criterio de radioterapia y corazón, con un intervalo de tiempo de los últimos 5 años hasta agosto 2020, escritos en inglés. Además, se buscaron referencias cruzadas y se incluyeron documentos de consenso de parte de sociedades de cardiología internacionales.
Abstract Radiation-Induced Heart Disease: Practical Implications for Its Prevention, Diagnosis, and Treatment The radiotherapy represents a very useful therapeutic tool for the treatment of different types of cancer. When it is used to treat thoracic lesions there is a risk of appliying a determined radiation dose to the heart and consequently develop cardiac complications. The adverse effects can be seen in distinct heart components and the manifestations can be appreciated mainly in the long term. Through an integral evaluation of the cardiovascular risk, the identification of concomitant therapies with cardiotoxic potential, the application of heart sparing radiotherapy techniques and the control with cardiac tests, it is intended to optimize the oncologic and cardiovascular outcomes of the patients. In those patients who present with cardiac complications, there are several therapeutic options ranging from chirurgic to percutaneous, which are challenging given the complexity of the cases. Finally, there are different considerations in regard to the management of patients with electronically implantable cardiaca devices. Search strategy: A search was carried out in Pubmed for articles under the criteria of radiotherapy and heart, with a time interval of the last 5 years until August 2020, written in English. In addition, cross-references were searched and consensus documents from international cardiology societies were included.
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Humans , Radiotherapy/adverse effects , Cardiotoxicity/prevention & control , Follow-Up Studies , Cardiotoxicity/diagnosis , Cardiotoxicity/therapy , Heart Disease Risk FactorsABSTRACT
Objective:To investigate the regulatory role of microRNA in radiation-induced heart disease (RIHD) in mice and provide a new strategy for its treatment.Methods:Based on the Gene Expression Omnibus database (GSE147241), which includes normal heart tissue and irradiation heart tissue, we conducted bioinformatics research and analysis to determine the differentially-expressed genes. Then, thirty male C57/BL6 mice were randomly divided into the control group, irradiation group and miR-133a overexpression intervention group. The heart received single dose of X-ray 20 Gy in the irradiation group and miR-133a overexpression intervention group, but not in the control group, and then fed for 16 weeks. Cardiac function was assessed by echocardiography. Myocardial fibrosis was detected by Masson staining. The expression levels of miR-133a, CTGF, COL-1 and COL-3 mRNA were detected by qRT-PCR. The expression levels of CTGF, COL-1 and COL-3 proteins were detected by western blot.Results:miR-133a was the differentially-expressed gene between the irradiation and control groups. Overexpression of miR-133a could mitigate the decrease in cardiac function and increase in myocardial collagen content ( P<0.01). Meantime, overexpression of miR-133a could down-regulate the expression levels of CTGF, COL-1, COL-3 mRNA and protein ( P<0.01). Conclusions:Radiation increases the synthesis of collagen and leads to myocardial fibrosis remodeling. Overexpression of miR-133a can alleviate the radiation-induced myocardial fibrosis.
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Radiation-induced heart disease includes various types of cardiac disorders that occur after thoracic irradiation therapy. The coronary artery has been known to be affected in this kind of pathological condition. A 37-year-old man diagnosed with acute coronary syndrome was referred to our institution. He had received irradiation therapy for mediastinal malignant lymphoma at the age of 10 and 11 years. An extended thymectomy for a thymoma via median sternotomy was performed at 18 years old. He also underwent thoracoscopic pericardial fenestration for a pericardial effusion at 26 years old. Coronary angiography revealed severe stenosis of the left and right coronary ostia. Considering the patient's characteristics, including a history of thoracic irradiation therapy, radiation induced heart disease was suspected as a pathogenesis for severe ostial stenosis of the coronary arteries. He underwent conventional on-pump beating coronary artery bypass grafting (CABG) on an urgent basis. Neither internal thoracic artery was suitable for bypass conduit because of dense adhesion. Therefore, the radial artery and great saphenous vein were used as free grafts for coronary revascularization. Furthermore, partial clamping of the ascending aorta seemed to be difficult and inappropriate owing to severe adhesion, so proximal anastomosis devices were used without a side biting clamp. The postoperative course was uneventful and both bypass grafts were patent. Now, he is doing well 10 years after the CABG without any other cardiac event.
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Myocardial fibrosis is a predominant pathological change of radiation-induced heart disease (RIHD) in late stage.It often occurs several or more than ten years after radiotherapy and can lead to myocardial remodeling, impaired cardiac function, and heart failure.At present there is no effective method to prevent or reverse the development of radiation-induced myocardial fibrosis.Many cells, cytokines, and other factors are involved in the development and progression of myocardial fibrosis in RIHD and some of them have been validated.But most investigators focused on the pathological changes and related mechanisms in early stage, and myocardial fibrosis was just regarded as an endpoint event.The definitive mechanisms of myocardial fibrosis in late stage remain unclear.This paper reveiws the studies about general mechanisms of myocardial fibrosis in RIHD and summarizes the roles of microcirculation dysfunction, mast cells, several cytokines, hypoxia, oxidative stress, and renin-angiotensin system, and points out the future research direction of the pathogenesis of myocardial fibrosis in RIHD.It provides new ideas for discovering the potential targets for clinical intervention of myocardial fibrosis in RIHD.
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Objective To examine the pathological changes in the myocardial tissues such as inflammatory response and fibrosis in a rat model of acute radiation-induced heart damage (RIHD),and to explore whether NF-κB and its downstream pathway are associated with acute radiation-induced myocardial fibrosis.Methods Fourteen nale adult Sprague-Dawley rats were randomly divided into control group and radiation group.Local heart irradiation was delivered to the precordial region of rats to establish an RIHD model in a single fraction with a dose of 20 Gy generated by a 6 MV linear accelerator.At 14 days after irradiation,the histopathological changes in myocardial and interstitial tissues were examined by HE staining;the distribution of collagen fibers was observed by Masson staining,and collagen volume fraction (CVF) was used as a semi-quantitative evaluation for myocardial collagen deposition,which was defined as the percentage of collagen area occupied in total area,and was compared using the independent-samples t test.The protein and mRNA expression levels of the NF-κB members p50 and p65 and the downstream pathway members hypoxia-inducible factor 1α(HIF-1o),connective tissue growth factor (CTGF),and type I (COL-1) were quantitatively analyzed by Western blot and qPCR,respectively.Results At 14 days after local heart irradiation,the radiation group showed significant myocardial edema and derangement,rupturc of some myocardial ceils,mild nuclear pyknosis,darkened nuclear staining,a small number of irregular nuclei,and myocardial interstitial inflammatory cell infiltration accompanied by increased fibroblast,as compared with the control group.The Masson staining showed that the collagen fibers in radiation group were widely distributed at the interstitial tissue and increased significantly compared with those in the control group;normal myocardial cells were in disordered array and had a tendency to be replaced by collagen fibers.The semi-quantitative analysis showed that radiation induced a significant increase in CVF (22.05％ vs.3.76％,P =0.003).Western blot and qPCR revealed that the protein and mRNA expression of p50,p65,HIF-1 α,CTGF,and COL-1 was significantly higher in the radiation group than in the control group (all P ＜ 0.05).Conclusions The pathological features of acute RIHD include significant myocardial edema and myocardial interstitial inflammatory cell infiltration accompanied by increased fibroblasts and collagen fibers.Radiation exposure can activate NF-κB and cause the upregulation of HIF-1α and CTGF at both protein and mRNA levels,which may play an important role in the progression of radiation-induced myocardial inflammation to fibrosis.
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Objective To observe myocardial tolerance to ischemia/reperfusion (I/R) injury in rats after exposure to X-ray irradiation.Methods Twelve male rats were randomly divided into control group and radiation group.The rat model of radiation-induced heart disease was established in the radiation group by precordial irradiation with 20.0 Gy of 6 MV X-ray in a single fraction.At 14 days after model establishment,the Langendorff perfusion technique was performed in the two groups and the cardiac parameters including left ventricular developing pressure (LVDP),left ventricular end diastolic pressure (LVEDP),maximal rate of left ventricular pressure rise/fall (+/-LVdp/dtmax),and coronary flow (CF)were recorded.Myocardial infarct size after I/R was compared between the two groups by 2,3,5-triphenyltetrazolium chloride staining.Results After 30 minutes of ischemia and 60 minutes of reperfusion,the irradiation group had a significantly slower CF than the control group (5.64±0.35 vs.8.38±0.52 ml/min,P=0.002).Moreover,the irradiation group had substantially poorer recovery of cardiac function in isolated hearts compared with the control group,as shown by a significantly reduced LVDP (25.4±2.31 vs.52.76±2.76 mm Hg(1 mm Hg=0.133 kPa),P=0.000),significantly reduced+/-LVdp/dtmax(547.04±78.74 vs.1 100.05±83.35 mm Hg(1 mm Hg=0.133 kPa)/s,P=0.001;-408.81±56.74 vs-813.62±73.82mm Hg(1 mm Hg =0.133 kPa)/s,P=0.002),and a significantly increased LVEDP (85.29±4.61 vs.65.65±3.65 mm Hg (1 mm Hg =0.133 kPa),P=0.012).X-ray irradiation induced a significantly increased percentage of myocardial infarct size in rats (44.67％±0.95％ vs.30.46％±0.96％,P=0.000).Conclusions X-ray irradiation can induce coronary injury,reduce myocardial tolerance to I/R injury,and increase myocardial infarct size after I/R in rats.
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Radiation therapy is one of the important comprehensive treatment strategies for thoracic neoplasms,but it also can cause radiation-induced heart disease (RIHD) which can affect the quality of life and even endanger the lives of patients while killing tumor.With the development of comprehensive treatment for cancer,the patients achieve better survival outcomes.And the study reported about RIHD increased as well,which made RIHD became an important complication of thoracic neoplasms' treatment.Though modem radiotherapy techniques and new therapeutic principles have significantly made the incidence of RIHD decreased,the harm of RIHD should not be ignored.In this article,we review the research progress of RIHD.
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Objective To investigate the pathological manifestations of acute?stage radioactive myocardial damage and related mechanisms using an experimental animal model. Methods A total of 12 adult male Sprague?Dawley rats were randomly divided into control group and radiation group. In the radiation group, the model of radiation?induced myocardial damage was established by the irradiation of the anterior myocardial territory with 6?MV X?ray at a single dose of 20 Gy, and at 14 days after irradiation, HE staining was used to observe the morphological changes of cardiomyocytes and intercellular matrix, and Masson staining was used to observe the distribution of collagen fibers. The collagen volume fraction ( CVF) was used for semi?quantitative analysis. ELISA was used to measure the activity of total superoxide dismutase ( T?SOD) and the concentration of malondialdehyde ( MDA ) , and Western blot was used to measure the expression of the fibrosis marker protein collagen type I ( COL?1 ) and the endoplasmic reticulum stress?related proteins GRP78 and CHOP. The t?test, t ’?test, or nonparametric rank sum test was used for comparison between groups. Results At 14 days after local irradiation of the heart, the radiation group had disordered arrangement of cardiomyocytes, marked edema, rupture of some cardiomyocytes, mild karyopyknosis in cardiomyocytes, and infiltration of inflammatory cells in the myocardial interstitium, compared with the control group. Collagen fibers in the myocardial tissue were mainly distributed in the perivascular area and cardiomyocyte interstitium. The radiation group had a significantly higher CVF than the control group ( 11?35% vs. 5?23%, P=0?000 ) and a significant increase in the expression of COL?1 compared with the control group ( P=0?000) . The radiation group had significant increases in the activity of T?SOD and the concentration of MDA in the myocardial tissue compared with the control group ( T?SOD:156?61 U/mgprot vs. 137?06 U/mgprot, P= 0?042;MDA:2?36 nmol/mgprot vs. 1?31 U/mgprot, P=0?007) . Compared with the control group, the radiation group showed significant increases in the expression of endoplasmic reticulum stress?related proteins GRP 7 8 and CHOP ( P= 0?037 and 0?009 ) . Conclusions The pathological manifestations of acute?stage myocardial damage include degeneration of cardiomyocytes, inflammatory exudation in the interstitium, and deposition of collagen in the perivascular area and myocardial interstitium. Myocardial fibrosis can be observed in the acute stage of radiation?induced myocardial damage, and the mechanism may be related to oxidative stress and endoplasmic reticulum stress induced by radioactive rays.
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OBJECTIVE: To determine the efficacy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the detection of radiation-induced myocardial damage in beagles by comparing two pre-scan preparation protocols as well as to determine the correlation between abnormal myocardial FDG uptake and pathological findings. MATERIALS AND METHODS: The anterior myocardium of 12 beagles received radiotherapy locally with a single X-ray dose of 20 Gy. 18F-FDG cardiac PET/CT was performed at baseline and 3 months after radiation. Twelve beagles underwent two protocols before PET/CT: 12 hours of fasting (12H-F), 12H-F followed by a high-fat diet (F-HFD). Regions of interest were drawn on the irradiation and the non-irradiation fields to obtain their maximal standardized uptake values (SUVmax). Then the ratio of the SUV of the irradiation to the non-irradiation fields (INR) was computed. Histopathological changes were identified by light and electron microscopy. RESULTS: Using the 12H-F protocol, the average INRs were 1.18 +/- 0.10 and 1.41 +/- 0.18 before and after irradiation, respectively (p = 0.021). Using the F-HFD protocol, the average INRs were 0.99 +/- 0.15 and 2.54 +/- 0.43, respectively (p < 0.001). High FDG uptake in irradiation field was detected in 33.3% (4/12) of 12H-F protocol and 83.3% (10/12) of F-HFD protocol in visual analysis, respectively (p = 0.031). The pathology of the irradiated myocardium showed obvious perivascular fibrosis and changes in mitochondrial vacuoles. CONCLUSION: High FDG uptake in an irradiated field may be related with radiation-induced myocardial damage resulting from microvascular damage and mitochondrial injury. An F-HFD preparation protocol used before obtaining PET/CT can improve the sensitivity of the detection of cardiotoxicity associated with radiotherapy.
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Animals , Dogs , Male , Fasting , Fluorodeoxyglucose F18/metabolism , Heart/diagnostic imaging , Heart Injuries/diagnostic imaging , Myocardium/metabolism , Positron-Emission Tomography/methods , Radiation Injuries/diagnosis , Thoracic Neoplasms/radiotherapy , Tomography, X-Ray Computed/methodsABSTRACT
Objective To evaluate the effect of TGF-β1 and IL-1β expression in serum on acute radiation-induced heart disease (RIHD) in patients with thoracic tumors.Methods Three-dimensional conformal radiotherapy (3D-CRT) or intensity modulated radiotherapy (IMRT) was delivered at 1.8-2.0 Gy,5 times per week to a total dose of 50-66 Gy to 44 patients with lung cancer and 10 patients with esophagus cancer.The target and organs at risk dose distribution were analyzed by 3-dimensiond treatment planning system.The expressions of TGF-β1 and IL-1β in serum were detected by enzyme linked immunosorbent assay before and at the end of the irradiation.The cardiac injury was evaluated by detecting the cmyocardium creatase,cardiac troponin I (cTnI),electrocardiogram and cardiac function before and at the end of the irradiation within 90 d.The acute RIHD was evaluated by the Common Terminology Criteria V 3.0 (NCI-CTCAE 3.0).The expressions of TGF-β1 and IL-1β in the serum of RIHD patients with thoracic tumors were analyzed.Results The expression of TGF-β1 in serum was (888.4 ± 41.1) μg/L before the irradiation and approached to (926.1 ± 23.1) μg/L at the end of the radiotherapy.The expression level of TGF-β1 in the serum of acute RIDH group was (900.6 ± 34.5) μg/L,higher than that of normal group [(865.7 ±47.0) μg/L,t =-2.646,P ＜0.05)].The acute RIDH was correlated with the expression level of TGF-β1 before irradiation and the difference before and at the end of irradiation (r =0.378,0.311,P ＜0.05).The IL-1β expression had no significant difference before and after irradiation.The expression of TGF-β1 in serum before and at the end of irradiation had positive correlation with the expression of IL-1β at the end of the irradiation (r =0.416,0.389,P ＜ 0.05).Conclusions The expression of TGF-β1 in the serum of patients with thoracic tumor increases after irradiation and correlated with the acute RIHD,but the expression of IL-1β in serum has no relationship with RIHD.TGF-β1 could induce the expression of IL-1β at the end of the irradiation.