Radiation-induced Cardiac Damage Research Articles

IL-33/soluble ST2 axis is associated with radiation-induced cardiac injury.

Radiotherapy for treating breast cancer is associated with cardiac damage. This study aimed to investigate the role of the interleukin (IL)-33/soluble receptor ST2 (sST2) axis in radiation-induced cardiac injury. Expressions of IL-33 and sST2 were detected in breast cancer patients following radiotherapy, radiation-induced cardiac damaged mice model, and cardiomyocytes using quantitative real-time PCR (qRT-PCR) and immunohistochemical assay. Cardiac injury was evaluated through an ultrasound imaging system and hematoxylin & eosin staining. The transcriptional factor was assessed using dual-luciferase reporter assay and chromatin immunoprecipitation. The results indicated that IL-33 and sST2 were highly expressed in breast cancer patients, which further elevated post-6 months but reduced after 12 months of radiotherapy. Radiation induces cardiac dysfunction and elevated IL-33 and sST2 levels in a time-dependent manner. However, silencing of IL-33 decreased sST2 expression to alleviate radiation-induced cardiac dysfunction. The IL-33 could be transcriptional activated by TCF7L2 by binding to IL33 promoter sites, which mutation alleviated cardiomyocyte injury caused by radiation. Additionally, radiation treatment resulted in higher levels of TCF7L2, IL-33, and sST2 in cardiomyocytes, and TCF7L2 knockdown reduced IL-33 and sST2 expression. In conclusion, TCF7L2 transcriptional-activated IL-33 mediated sST2 to regulate radiation-induced cardiac damage, providing novel insights into radiotherapy-induced cardiac damage.

Abstract 14676: Susceptibility to Cardiac-Targeted Irradiation in Wild-Type and Nos1 Haploinsufficient Mice

Introduction: Cardiac irradiation causes heart failure and arrhythmias. We reported that cardiac-targeted irradiation (CTI) led to cardiac dilation with increased end diastolic volume (EDV) by echocardiogram (echo) after 9 months in wild-type C57Bl6/J (WT) male (M) but not female (F) mice. Both sexes developed cardiac fibrosis and evidence of lung congestion, and the radiation mitigator MMS350 did not protect either sex. Here, we studied the effect of CTI on Nitric Oxide Synthase 1 haploinsufficient (Nos +/- ) mice treated with/without MMS350. Methods: 10 week-old Nos +/- and WT mice were exposed to 20 Gy CTI (R) with or without MMS350 (D) and followed for 9 months (Nos +/- : +R+D, n = 9M, 6F; +R-D, n = 6M, 7F; WT: +R+D, n = 12M, 14F; +R-D, n = 13M, 14F), with parallel unirradiated controls (Nos +/- : -R+D, n = 8M, 6F; -R-D, n = 10M, 7F; WT: -R+D, n = 8M, 12F; -R-D, n = 7M, 8F)). Echos and EKGs were performed at baseline and every 3 months. Heart weight (HW), lung weight (LW), and body weight (BW) were measured. Results: Unlike irradiated male WT mice where EDV was increased (p=0.001), EDV was smaller in male (p=0.04) and EF was decreased in both male (p=0.01) and female (p=0.05) Nos +/- irradiated mice compared to unirradiated controls, independent of MMS350 treatment (Figure). In addition, the PR interval was shorter in irradiated Nos +/- male (p=0.008) and female (p=0.003) mice compared to unirradiated controls. HW/BW was not significantly changed in any group, while LW/BW was significantly increased only in WT male (p=0.04) and female (p=0.001) irradiated mice. Conclusions: In long term follow-up of CTI-treated mice, Nos1 deficiency prevents sex-specific cardiac dilation in males, promotes left ventricular systolic dysfunction and alters cardiac conduction system properties. Further investigation into the role of nitric oxide in radiation-induced cardiac damage and the mechanisms underlying sex differences in the response to radiation are warranted.

Urinary Metabolomics for the Prediction of Radiation-Induced Cardiac Dysfunction.

Survivors of acute radiation exposure are likely to experience delayed effects that manifest as injury in late-responding organs such as the heart. Non-invasive indicators of radiation-induced cardiac dysfunction are important in the prediction and diagnosis of this disease. In this study, we aimed to identify urinary metabolites indicative of radiation-induced cardiac damage by analyzing previously collected urine samples from a published study. The samples were collected from male and female wild-type (C57BL/6N) and transgenic mice constitutively expressing activated protein C (APCHi), a circulating protein with potential cardiac protective properties, who were exposed to 9.5 Gy of γ-rays. We utilized LC-MS-based metabolomics and lipidomics for the analysis of urine samples collected at 24 h, 1 week, 1 month, 3 months, and 6 months post-irradiation. Radiation caused perturbations in the TCA cycle, glycosphingolipid metabolism, fatty acid oxidation, purine catabolism, and amino acid metabolites, which were more prominent in the wild-type (WT) mice compared to the APCHi mice, suggesting a differential response between the two genotypes. After combining the genotypes and sexes, we identified a multi-analyte urinary panel at early post-irradiation time points that predicted heart dysfunction using a logistic regression model with a discovery validation study design. These studies demonstrate the utility of a molecular phenotyping approach to develop a urinary biomarker panel predictive of the delayed effects of ionizing radia-tion. It is important to note that no live mice were used or assessed in this study; instead, we focused solely on analyzing previously collected urine samples.

Evaluating the Mitigation Effect of Spirulina Against Radiation-Induced Heart Injury.

During a radiological or nuclear disaster, exposure to a high dose of ionizing radiation usually results in cardiovascular diseases such as heart failure, attack, and ischemia. The purpose of this study was to examine the mitigation effects of Spirulina in comparison to Metformin's. 25 male Wistar rats were randomly assigned to five groups (5 rats in each): for the control group, rats did not receive any intervention. In group 2, spirulina was administered orally to rats. In group 3, rats were irradiated to the chest region with 15 Gray(Gy) x-radiation. In groups 4 and 5, rats were irradiated in the same way as group 3. Forty-eight hours after irradiation, treatment with Spirulina and Metformin began. All rats were sacrificed after ten weeks, and their heart tissues were removed for histopathological and biochemical assays. Results showed an elevation in Malondialdehyde (MDA) and decreasing superoxide dismutase (SOD) activity. Moreover, pathological changes of radiation were irregularities in the arrangement of myofibrils, proliferation, migration of mononuclear cells, vacuolation of the cytoplasm, and congestion. Administration of spirulina enhanced the SOD activity while did not affect MDA level and pathological change in heart tissue. Despite spirulina, metformin had a considerable effect on pathological lesions and decreased the level of MDA. Reactive oxygen species (ROS) may be involved in the late effects of radiationinduced heart injury, and scavenging these particles may contribute to reduced radiation side effects. Based on these results, Spirulina had no effect on radiation-induced cardiac damage, while metformin did. Higher Spirulina doses given over a longer period of time will likely have a greater heart-mitigate effect.

New insights into the development of radiation-induced cardiac damage using a mouse model

Abstract Background The improvement of anticancer-therapy results in a greater amount of long-term survivors after radiotherapy. Therefore, the understanding of cardiotoxicity after irradiation is of increasing importance. Long-term adverse cardiovascular events may become evident years or decades after radiotherapy. The relative contribution of irradiation in relation to other cancer treatments can often only be estimated. Recent experimental and clinical evidence suggests that cardiovascular symptoms, including exertional dyspnoea, may be caused by heart failure with preserved ejection fraction (HFpEF), which remains incompletely understood in patients after radiation therapy. Purpose We aim to characterize the development of radiation-induced cardiomyopathy and elucidate underlying patho-mechanisms. Methods Mice received a single dose of whole thorax irradiation (12.5 Gy) and were sacrificed at 1 and 3 days or 3, 6, 12, 16, 20 and 25–30 weeks. Endothelial cells and immune cells at different time points were quantified using flow cytometry (FACS). Structural changes and localization of endothelial cell damage was imaged using light-sheet fluorescence microscopy (LSFM) with CD31 staining. Development of fibrosis was determined using qRT-PCR (fibronectin and TGFβ), western blot (collagen-1,α-smooth muscle) and (immune-)histological analyses. Functional analyses were conducted using echocardiography and pressure-volume-(PV-)catheterization. Results Endothelial damage was determined by significant reduction of CD31 expression in mouse hearts 6 weeks after irradiation compared to sham-treated control mice using FACS analyses. LSFM showed structural changes especially in the edge zone of left ventricle presented as less densely CD31 stained regions. Additionally, we investigated cardiac immune cell response regarding innate and adaptive immunity, showing specific response to tissue damage at different time points. Invasion of monocytes started 6 weeks after irradiation and highest level of monocytes and macrophages was measured at 12 weeks. Regarding cardiac long-term damage, myocardial fibrosis was detected on RNA- and protein-level as well as in histological analyses with significant changes 20 weeks after chest irradiation. This could be correlated with echocardiographic parameters for diastolic dysfunction (elevated isovolumic relaxation time/mitral valve deceleration time). Also functional reserve of irradiated mice was reduced, investigated by measurement of cardiac output and stroke volume after dobutamine injection in PV-catheterization. Conclusion We described a novel time-dependent endothelial cell damage and immune cell response after thoracic irradiation in mice, which could also be imaged using LSFM. Characterization of long-term damage showed cardiac fibrosis correlating with diastolic dysfunction and reduced contractile reserve. Furthermore, therapeutic approaches will be investigated using the established mouse model. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Dr. S.M. Mrotzek acknowledges the following funding source: IFORES research grant from the Medical Faculty, University Duisburg-Essen, Germany.

The effect of selected drugs on the mitigation of myocardial injury caused by gamma radiation.

Radiation damage of healthy tissues represents one of the complications of radiotherapy effectiveness. This study is focused on the screening of potentially effective drugs routinely used in medical practice and involved in the mechanism of radiation injury, namely for radiation-induced production of free radicals in the body. Experiments in rats revealed significant reduction of oxidative stress (malondialdehyde) and inflammatory marker (tumor necrosis factor α) in 10 Gy irradiated groups after administration of atorvastatin and a slight decrease after tadalafil administration, which indicates that one of the possible mechanisms for mitigation of radiation-induced cardiac damage could be the modulation of nitric oxide (NO) in endothelium and phosphodiesterase 5. In addition, miRNAs were analyzed as potential markers and therapeutically effective molecules. Expression of miRNA-21 and miRNA-15b showed the most significant changes after irradiation. Atorvastatin and tadalafil normalized changes of miRNA (miRNA-1, miRNA-15b, miRNA-21) expression levels in irradiated hearts. This screening study concludes that administration of specific drugs could mitigate the negative impact of radiation on the heart, but more detailed experiments oriented to other aspects of drug effectiveness and their exact mechanisms are still needed.

The Troponin-I Release in Patients with Left-Sided Early-Stage Breast Cancer Undergoing Adjuvant Whole Breast Radiotherapy: An Iranian Experience

Background: Breast cancer is the most frequent cancer among women. In line with the survival improvement of patients with cancer, the issue of treatment-induced toxicities becomes more important. Objectives: This study aimed at evaluating acute radiation-induced cardiac damage. Methods: Between 2016 and 2019, women with histologically-confirmed early-stage left-sided breast cancer or ductal carcinoma in-situ (DCIS) without prior chemotherapy, who were candidates for adjuvant whole breast radiotherapy, entered the study. The radiation-induced cardiotoxicity was assessed, using a rise in high-sensitivity cardiac troponin I (hscTnI) over the radiotherapy. Likewise, the association between the percentage of heart receiving at least 25Gy (V25Gy) and the rise in hscTnI was evaluated as the secondary endpoint. Results: A total of 22 women were included in this study. Mean ± standard deviation (SD) hscTnI for the whole study population was 12 ± 2 ng/L before and 15 ± 2 ng/L after radiotherapy. The median (interquartile range [IQR]) V25Gy was 8.05% (6.95% - 8.95%). The difference between hscTnI levels before and after radiotherapy was significant (P = 0.001). There was no correlation between V25Gy and the rise in hscTnI (P = 0.18). Conclusions: hscTnI is a sensitive marker to detect early radiation-induced cardiotoxicity. There is no association between V25Gy and the rise in hscTnI over radiotherapy.

The effects of microgravity and space radiation on cardiovascular health: From low-Earth orbit and beyond.

The unique conditions of space harbor considerable challenges for astronauts to overcome. Namely, the ionizing content of space radiation and the effects of microgravity have been implicated in the pathogenesis of cardiovascular disease. Post-flight carotid arterial stiffness was demonstrated in astronaut studies while early arteriosclerosis has been linked with microgravity-induced oxidative stress in cellular studies. Similarly, radiation has been shown to disrupt molecular pathways, enhance reactive oxygen species and increase risk of cardiovascular disease in exposed populations. These results may bear even more significance in space owing to the propensity for microgravity and space radiation to yield synergistic and/or additive interactions. Potential countermeasures such as α-tocopherol and captopril target these oxidative pathways and may help to protect against the effects of microgravity and radiation-induced cardiac damage. However, more research needs to be conducted in this area to facilitate a safe passage for humans to the Moon, Mars and beyond.

Sodium tanshinone IIA sulfonate prevents radiation-induced damage in primary rat cardiac fibroblasts.

This study investigated the effects of X-ray irradiation on primary rat cardiac fibroblasts (CFs) and its potential mechanism, as well as whether sodium tanshinone IIA sulfonate (STS) has protective effect on CFs and its possible mechanism. Our data demonstrated that X-rays inhibited cell growth and increased oxidative stress in CFs, and STS mitigated X-ray-induced injury. Enzyme-linked immuno-sorbent assay showed that X-rays increased the levels of secreted angiotensin II (Ang II) and brain natriuretic peptide (BNP). STS inhibited the X-ray-induced increases in Ang II and BNP release. Apoptosis and cell cycle of CFs were analyzed using flow cytometry. X-rays induced apoptosis in CFs, whereas STS inhibited apoptosis in CFs after X-ray irradiation. X-rays induced S-phase cell cycle arrest in CFs, which could be reversed by STS. X-rays increased the expression of phosphorylated-P38/P38, cleaved caspase-3 and caspase-3 as well as decreased the expression of phosphorylated extracellular signal-regulated kinase 1/2 (ERK 1/2)/ERK 1/2 and B cell lymphoma 2 (Bcl-2)/Bcl-2 associated X protein (BAX) in CFs, as shown by Western blotting. STS mitigated the X-ray radiation-induced expression changes of these proteins. In conclusion, our results demonstrated that STS may potentially be developed as a medical countermeasure to mitigate radiation-induced cardiac damage.

Bradykinin-potentiating factor isolated from Leiurus quinquestriatus scorpion venom alleviates cardiomyopathy in irradiated rats via remodelling of the RAAS pathway.

The objective of this work was to evaluate the effect of a bradykinin-potentiating factor (BPF) isolated from Leiurus quinquestriatus scorpion venom as a natural modulator of radiation-induced cardiac damage. Four groups of rats were treated as follows; control group, group receiving BPF (1µg/g b.wt i.p./biweekly) for 4weeks, group irradiated at 6Gy, group receiving BPF post-irradiation for 4weeks. Irradiation induced a significant elevation of myocardial parameters: atrial natriuretic peptide (ANP), cardiac troponin I (cTnI), potassium (K+ ) and creatine kinase (CK); vascular indices: lactate dehydrogenase (LDH), inducible nitric oxide synthase (iNOS) and endothelin I; oxidative stress indices: malondialdehyde (MDA) associated with a significant depletion of both reduced glutathione (GSH) in the cardiac tissue homogenate and serum ferric reducing antioxidant power (FRAP) depletion and significantly reinforced elevation of Renin Angiotensin Aldosterone System (RAAS) indices: serum angiotensin II (AngII) and aldosterone, and also protein expression of cleaved caspase-3 and cyclophilin A. BPF administration altered the biochemical damage of radiation, specifically inhibited AngII formation, aldosterone release and prevented the histopathological and immunohistochemical alterations which were observed in cardiac tissue with significant reduction in mean arterial blood pressure (MAP) caused by irradiation. In conclusion, biochemical assays, histopathological and immunohistochemical findings of the present study demonstrated that exogenous BPF isolated from scorpion venom reduced the cardiomyopathy alterations induced by irradiation via remodelling of the RAAS pathway.

Research progress of radiation-induced heart injury—clinical

At present, the heart has become an important organ at risk during radiotherapy for thoracic, mediastinal and breast carcinoma. Heart is relatively sensitive to radiation because of its anatomical location and structure. Long-term survival of patients have been affected by cardiac adverse effect post-radiotherapy. In this paper, the progress of clinical manifestations, risk factors, screening methods, prevention and treatment of radiation-induced cardiac damage were reviewed as follows. Key words: Radiation-induced heart injury; Research progress

3173 A Mouse Model to Study Image-Guided, Radiation-Induced Cardiac Injury and Potential Clinically Targetable Biologic Mediators

OBJECTIVES/SPECIFIC AIMS: The overall objective of this study is to develop a novel, clinically-relevant, image-guided mouse model for radiation-induced cardiotoxicity, which can be used to gain insight into clinically-targetable, pathophysiologic mechanisms of cardiac injury in thoracic radiotherapy patients. METHODS/STUDY POPULATION: Photon or sham radiation will be administered at differential doses to a defined portion of the heart and/or lungs of C57BL/6 female mice using micro-CT visualization of the heart with Xstrahl’s MuriSlice Software applied to the Small Animal Radiation Research Platform (SARRP). Cardiac and lung segments from a subset of mice will be harvested at specific time points for confirmation of radiation targeting, local apoptosis assessment, and evaluation of fibrosis and vascular tissue morphology. Quantitative echocardiography, myocardial 18F-fluorodeoxyglucose positron emission tomography computed tomography (18F-FDG PET/CT), and myocardial perfusion imaging (MPI) with Technicium-99 (Tc-99) sestamibi will be implemented to identify sensitive imaging measures of cardiac injury and asses myocardial mechanics, inflammation, and perfusion deficits, respectively. Concurrently, a multiparametric analysis will be conducted to identify novel, circulating biomarkers of cardiotoxicity. RESULTS/ANTICIPATED RESULTS: We hypothesize that a clinically-relevant mouse model can be generated by the in situ, focal irradiation of a portion of heart and/or lung tissue segments, and can be used to elucidate molecular mechanisms of radiation-induced cardiac damage. We anticipate time-dependent and dose-dependent, focal histopathologic changes in the mouse heart, with cardiac fibrosis development, vascular damage, and cellular apoptosis in irradiated mice. Additionally, we anticipate that our mouse model of focal heart irradiation will reveal radiologic and biochemical changes that can be used to characterize and predict radiation-induced cardiac injury. Specifically, we expect our quantitative echocardiography, FDG-PET, and MPI parameters to identify and characterize cardiac damage that topographically matches histopathological analysis, and expect levels of select biochemical markers to differentially vary with time. DISCUSSION/SIGNIFICANCE OF IMPACT: Our mouse model of radiation-induced cardiotoxicity has the potential to shift current preclinical research paradigms to more closely mimic the radiation plans most commonly administered in clinical practice. The primary technologic innovation to be developed here is the use of the SARRP to deliver image-guided, in situ, focal radiation to a defined portion of the mouse heart. From a conceptual perspective, we propose a novel approach for phenotyping radiation-induced cardiac damage in patients undergoing chest radiation therapy, integrating sensitive radiomic and biochemical markers into a predictive model of cardiotoxicity.

Cardiac radiation exposure associated with breast cancer radiotherapy: Dose distribution to the heart substructures and coronary arteries (BACCARAT study)

Radiotherapy (RT) is a major component of breast cancer treatment and advanced RT techniques allowed reducing irradiation of healthy tissue. However, the heart often remains partially exposed. Detailed individual heart dosimetry information is required to better understand radiation-induced cardiac damage. To analyze the distribution of individually-determined radiation dose to the heart and its substructures, in particular coronary arteries, after RT in breast cancer patients from the BACCARAT study. BACCARAT is a monocentric prospective cohort study that included unilateral breast cancer patients treated with RT between 2015 and 2017 and followed for 2 years with repeated cardiac imaging examinations, including coronary computed tomography angiography. Using the 3D dose matrix generated during RT treatment planning and the added coronary contours, dose distributions were generated for the following cardiac structures: whole heart, left ventricle (LV), left main coronary artery (LM), left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA). A descriptive analysis of the physical doses in Gray (Gy) was performed. Dose distributions were generated for 59 patients (50 left-sided breast cancer, 9 right-sided) who all received a treatment of 50 Gy to the breast. The mean heart dose was 2.98 Gy for left sided patients and 0.42 Gy for right sided and mean LV doses were respectively 6.23 Gy and 0.09 Gy. For left-sided patients, mean dose to LM (D_LM) = 1.29 Gy, D_LAD = 16.32 Gy, D_LCX = 1.59 Gy and D_RCA = 0.67 Gy, whereas corresponding doses for right-sided patients were D_LM = 0.35 Gy, D_LAD = 0.11 Gy, D_LCX = 0.14 Gy and D_RCA = 1.10 Gy. For left sided patients, the most exposed part of the LAD could receive doses > 45 Gy. Our study illustrates the wide range of doses experienced by the heart substructures and thus the poor significance of the mean heart dose as a radiation damage indicator.

Abstract 845: Acute irradiation exposure induces long-term cardiac adverse effects in the spontaneously hypertensive rat

Abstract Radiation-induced heart disease (RIHD) presents a significant challenge in the oncology setting. For instance, patients receiving acute doses of irradiation to the thoracic cavity for Hodgkin's lymphoma or breast cancer are subject to an elevated risk of RIHD. Excessive oxidative stress, at least in part, is responsible for some of the tissue damage. The ability to monitor and mitigate the long-term cardiac effects of radiation exposure in these populations by modulating oxidative stress has the potential to lead to improved health outcomes. We utilized the spontaneously hypertensive rat (SHR), which has proven a good model for drug-induced cardiotoxicity, to evaluate irradiation-induced heart damage. SHRs were exposed to low, medium, or high doses of full-body irradiation. Necropsy was performed to collect serum and tissue samples at two and four weeks post-irradiation, as well as followed for one year. Four weeks following gamma irradiation, both males and females showed decreased heart mass and decreased whole body mass after exposure to medium and high doses of radiation and these decreases were sustained in the high dose groups after one year. Serum cardiac troponin I and T analysis revealed signs of cardiomyopathy in both the medium and high dose groups at early time points and this signal was sustained in some animals up to one year later. Echocardiography revealed functional changes in cardiac performance including an increase in left ventricular volume at diastole in males and a decrease in left ventricular mass. Low red blood cell count indicated sustained anemic conditions in both males and females receiving the highest dose of irradiation, yet males appeared to be more sensitive. Levels of pro-inflammatory IL-6 were elevated at four weeks in males receiving the high dose. Finally, multiple animals receiving radiation developed spontaneous tumors after one year. We are currently investigating the oxidative stress-mediated molecular mechanisms behind the radiation-induced cardiac damage. Citation Format: Elliot T. Rosen, Dmitry Kryndushkin, Baikuntha Aryal, Yanira Gonzalez, Leena Chehab, Jennifer Dickey, Steven Mog, V Ashutosh Rao. Acute irradiation exposure induces long-term cardiac adverse effects in the spontaneously hypertensive rat [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 845.

Assessment of the onset of radiation-induced cardiac damage after radiotherapy of breast cancer patients

ObjectivesThe study aimed to evaluate the dose delivered to the heart during radiotherapy of left-sided and right-sided breast cancer (BC) patients, correlate the dose and laterality of radiotherapy to the possible cardiac damage and evaluate whether Left-ventricular Ejection Fraction (LVEF), Troponin-I (TnI), Creatinine Kinase (CK), Creatine Kinase-MB Relative Index (CK-MBRI) or Lactic Dehydrogenase (LDH) could be used to detect the possible onset of radiotherapy-related cardiotoxicity. Subjects and methods80 females were assigned as; 30 left-sided BC patients, 30 right-sided BC patients and 20 healthy females. Patients were treated by radical mastectomy followed by FAC-based chemotherapy and radiotherapy. CT-based 3D-planning was used to generate cardiac dose-volume histograms to assess mean dose received by the heart.Echocardiography was done to all patients before and 1 year after completing radiotherapy. In serum, TnI and CK-MB concentration and CK and LDH activities were determined before and 1 year after radiotherapy. ResultsIn left-sided patients, mean dose delivered to the heart was significantly higher in left-sided patients with significant association with total radiotherapy dose in left- but not right-sided patients. LVEF before and after radiotherapy were statistically different only in left-sided patients. LVEF one year after radiotherapy dropped 20% or more (ΔLVEF) in 6 patients, all were left-sided.Using cut-off values 0.08 ng/mL for TnI and 1.4 for CK-MBRI; 11 left-sided patients had abnormal TnI and CK-MBRI vs 5 right-sided patients, the 6 patients identified with ΔLVEF ≥ 20 were all among them. Conclusionthe mean dose delivered to the heart is significantly higher in left-sided patients, and it was correlated to the total radiotherapy dose. One year after radiotherapy, ΔLVEF is possibly good marker of cardiotoxicity onset, however, the persistent elevation of both TnI and CK-MBRI could identify both patients with cardiotoxicity and patients that are thought to be in subclinical phase of cardiac damage.

Protection of neonatal rat cardiac myocytes against radiation-induced damage with agonists of growth hormone-releasing hormone

Despite the great clinical significance of radiation-induced cardiac damage, experimental investigation of its mechanisms is an unmet need in medicine. Beneficial effects of growth hormone-releasing hormone (GHRH) agonists in regeneration of the heart have been demonstrated. The aim of this study was the evaluation of the potential of modern GHRH agonistic analogs in prevention of radiation damage in an in vitro cardiac myocyte-based model.Cultures of cardiac myocytes isolated from newborn rats (NRVM) were exposed to a radiation dose of 10Gy. The effects of the agonistic analogs, JI-34 and MR-356, of human GHRH on cell viability, proliferation, their mechanism of action and the protein expression of the GHRH/SV1 receptors were studied.JI-34 and MR-356, had no effect on cell viability or proliferation in unirradiated cultures. However, in irradiated cells JI-34 showed protective effects on cell viability at concentrations of 10 and 100nM, and MR-356 at 500nM; but no such protective effect was detected on cell proliferation. Both agonistic analogs decreased radiation-induced ROS level and JI-34 interfered with the activation of SAFE/RISK pathways. Using Western blot analysis, a 52kDa protein isoform of GHRHR was detected in the samples in both irradiated and unirradiated cells.Since GHRH agonistic analogs, JI-34 and MR-356 alleviated radiation-induced damage of cardiac myocytes, they should be tested in vivo as potential protective agents against radiogenic heart damage.

Abstract 3328: Mitigating long-term cardiac adverse effects of radiation exposure: Emerging opportunities in protein oxidation and autophagy modulation

Abstract Radiation-induced heart disease (RIHD) presents a significant challenge in the oncology setting. Patients who receive acute doses of irradiation to the thoracic cavity for Hodgkin's Lymphoma and breast cancer are subject to an elevated risk of RIHD. The ability to mitigate the long-term cardiac effects of radiation exposure in these populations by modulating protein oxidation and the process of autophagy in the heart has the potential to lead to improved health outcomes. We utilized the spontaneously hypertensive rat (SHR), which has proven a good model for drug-induced cardiotoxicity, to evaluate radiation-induced heart disease. SHRs were exposed to low, medium, or high doses of full-body irradiation. Necropsy was performed to collect serum and tissue samples at various time points up to one year. Echocardiography and electrocardiography were performed to evaluate functional changes in cardiac performance. Four weeks following ionizing radiation, both males and females showed decreased heart mass and decreased whole body mass in the groups exposed to medium and high doses of radiation. A marked difference in both heart and whole body mass was observed in the high dose group after one year. Anemic conditions were noted by low red blood cell counts observed in both males and females at all three time points in the animals receiving the highest dose of irradiation. Cardiac troponin T analysis revealed cardiotoxicity in both the medium and high dose groups at early time points. Echocardiography revealed that left ventricular volume at diastole was increased in males following high dose irradiation, and that left ventricular mass decreased following high irradiation exposures. Finally, it should also be noted that after one year, multiple animals receiving radiation developed spontaneous tumors. We are currently exploring the oxidative stress-mediated molecular mechanisms behind the radiation-induced cardiac damage and the subsequent, protective autophagic response. Citation Format: Elliot T. Rosen, Dmitry Kryndushkin, Yanira Gonzalez, Baikuntha Aryal, Leena Chehab, Jennifer Dickey, Ashutosh Rao. Mitigating long-term cardiac adverse effects of radiation exposure: Emerging opportunities in protein oxidation and autophagy modulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3328. doi:10.1158/1538-7445.AM2015-3328

Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis

BackgroundCardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target. MethodsThe size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes. ResultsIn patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca2+ transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals. ConclusionEpac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart.

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions

Cancer is diagnosed in >12 000 children and adolescents in the United States each year.1 Progress in cancer therapeutics over the past 40 years has remarkably improved survival rates for most childhood malignancies. For all pediatric cancers, 5-year survival increased from 58% for children diagnosed between 1975 and 1977 to 82% for those diagnosed between 1999 and 2006.2 In the United States, this success translates into >325 000 survivors of childhood cancer, of whom 24% are now >30 years from diagnosis.3 During this same period, the incidence of many histological subtypes of childhood cancer has increased, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia, non-Hodgkin lymphoma, neuroblastoma, and soft-tissue and germ-cell tumors.3 Consequently, the number of childhood cancer survivors is expected to increase as a result of the rising pediatric cancer incidence and improved long-term survival rates.3 The increasing number of survivors soon revealed acute and delayed modality-specific toxicities and their impact on quality of life and early mortality. In their seminal 1974 publication, Meadows and D’Angio4 described the wide array of potential late effects of successful therapy for childhood cancer. In the past 2 decades, the Childhood Cancer Survivor Study has also improved our understanding of the long-term mortality and morbidity in this high-risk population. Among young adult survivors of childhood cancer diagnosed between 1970 and 1986, at least 1 of 6 domains of health status (general health, mental health, functional status, activity limitations, cancer-related pain, and cancer-related anxiety) declined moderately to severely in 44%.5 The cumulative incidence of a chronic health condition 30 years after cancer diagnosis is now 73%, with a cumulative incidence of 42% for severe, disabling, or life-threatening conditions or death attributable to a chronic condition.6 Also by 30 years after cancer diagnosis, the cumulative mortality rate from causes …

Endoglin Haplo-Insufficiency Modifies the Inflammatory Response in Irradiated Mouse Hearts without Affecting Structural and Mircovascular Changes

BackgroundIt is now widely recognized that radiotherapy of thoracic and chest wall tumors increases the long-term risk of cardiovascular damage although the underlying mechanisms are not fully elucidated. There is increasing evidence that microvascular damage is involved. Endoglin, an accessory receptor for TGF-β1, is highly expressed in damaged endothelial cells and may play a crucial role in cell proliferation and revascularization of damaged heart tissue. We have therefore specifically examined the role of endoglin in microvascular damage and repair in the irradiated heart.Materials & MethodsA single dose of 16 Gy was delivered to the heart of adult Eng+/+ or Eng+/− mice and damage was evaluated at 4, 20 and 40 weeks, relative to age-matched controls. Gated single photon emission computed tomography (gSPECT) was used to measure cardiac geometry and function, and related to histo-morphology, microvascular damage (detected using immuno- and enzyme-histochemistry) and gene expression (detected by microarray and real time PCR).ResultsGenes categorized according to known inflammatory and immunological related disease were less prominently regulated in irradiated Eng+/− mice compared to Eng+/+ littermates. Fibrosis related genes, TGF-β1, ALK 5 and PDGF, were only upregulated in Eng+/+ mice during the early phase of radiation-induced cardiac damage (4 weeks). In addition, only the Eng+/+ mice showed significant upregulation of collagen deposition in the early fibrotic phase (20 weeks) after irradiation. Despite these differences in gene expression, there was no reduction in inflammatory invasion (CD45+cells) of irradiated Eng+/− hearts. Microvascular damage (microvascular density, alkaline phosphatase and von-Willebrand-Factor expression) was also similar in both strains.ConclusionEng+/− mice displayed impaired early inflammatory and fibrotic responses to high dose irradiation compared to Eng+/+ littermates. This did not result in significant differences in microvascular damage or cardiac function between the strains.