Radiation-induced Heart Damage Research Articles

Aloe Emodin Alleviates Radiation-Induced Heart Disease via Blocking P4HB Lactylation and Mitigating Kynurenine Metabolic Disruption.

Aloe emodin is an anthraquinone of traditional Chinese medicine monomer, which plays a protective action in cardiovascular diseases. However, the regulatory mechanisms of aloe emodin in the protection of radiation-induced heart damage (RIHD) are unclear. As a novel post-translational modification, lactylation is considered as a critical mediator in inflammatory cascade and cardiac injury. Here, using a cross of differential omics and 4D label-free lactylation omics, protein disulfide-isomerase (P4HB) is identified as a novel target for lactylation, and aloe emodin inhibits the binding of lactate to the K311 site of P4HB. Aloe emodin stabilizes kynurenine metabolism through inhibition of aspartate aminotransferase (GOT2) accumulation on damaged mitochondria. Mechanistically, aloe emodin inhibits phosphorylated glycogen synthase kinase 3B (p-GSK3B) transcription in the nucleus to repress the interaction of prostaglandin G/H synthase 2 (PTGS2) with SH3 domain of SH3 domain-containing GRB2-like protein B1 (SH3GLB1), thereby disrupting the functions of mitochondrial complexes and reducing SH3GLB1-mediated mitoROS accumulation, eventually suppressing calcium-binding and coiled-coil domain-containing protein 2 (NDP52)-induced mitophagy. This study unveils the regulatory role of aloe emodin in RIHD alleviation through PTGS2/SH3GLB1/NDP52 axis, indicates aloe emodin stabilizes GOT2-mediated kynurenine metabolism through P4HB lactylation. Collectively, this study provides novel insights into the regulatory mechanisms underlying the protective role of aloe emodin in cardiac injury, and opens new avenues for therapeutic strategies of aloe emodin in preventing RIHD by regulating lactylation.

Quantitative evaluation of radiation-induced heart disease in patients with lung cancer: a three-dimensional speckle tracking imaging study.

Adverse cardiovascular events due to radiation-induced heart disease (RIHD) have become the leading cause of death in cancer survivors, and early screening for RIHD has become an important clinical issue. Our objective was to determine the utility of three-dimensional speckle tracking echocardiography (3D-STE) for detecting RIHD. According to inclusion and exclusion criteria, patients with lung cancer who received radiotherapy in our hospital for the first time were recruited as subjects. All subjects underwent the conventional echocardiography and 3D-STE examination at six time points (1 day before radiotherapy, 2.5-3 and 5-6 weeks after beginning radiotherapy, and 3-, 6- and 12-month after ending radiotherapy). Routine electrocardiogram, serum cardiac troponin I (cTnI) and clinical data were detected simultaneously. A total of 105 patients with lung cancer were included in the study. Conventional echocardiography found a small amount of pericardial effusion occurred in 8 subjects at 5-6 weeks after beginning radiotherapy. 3D-STE showed that, compared with before radiotherapy, the absolute values of global longitudinal strain (GLS) and global strain (GS) were significantly decreased at 5-6 weeks after beginning radiotherapy (PGLS<0.001, PGS=0.002), and the absolute values of GLS, global radial strain, global circumferential strain, GS were gradually decreased further at 3-, 6- and 12-month after ending radiotherapy (P<0.001). Electrocardiograph showed that 32 subjects had electrocardiograph abnormalities during radiotherapy and 3 had electrocardiograph abnormalities at 3-month after ending radiotherapy, and most returned to normal within 6 months after ending radiotherapy. Patients with lung cancer undergoing radiation therapy have shown a decrease in the function of the left ventricle of the heart while receiving treatment. Combining the assessment of cTnI with GLS can enhance the early detection of radiation-induced heart damage.

Sirtuin 2 Exerts Regulatory Functions on Radiation-Induced Myocardial Fibrosis in Mice by Mediating H3K27 Acetylation of Galectin-3 Promoter.

Sirtuin 2 (SIRT2) and galectin-3 have been shown to protect the heart against fibrosis. However, their impacts on radiation-induced myocardial fibrosis (RIMF) remain to be elucidated. To deepen this understanding, the current study sought to explore the effects of SIRT2 and galectin-3 on RIMF and the underlying mechanisms. Galectin-3 knockout mice were obtained, and a radiation-induced heart damage (RIHD) mouse model was induced by local radiation exposure to the heart. Lentivirus transfection was then performed, and heart function, fibrosis of heart tissues, and levels of SIRT2, galectin-3, and fibrosis-related markers collagen type-I/-III and matrix metalloproteinase (MMP)2/MMP9 were respectively assessed by echocardiography, hematoxylin-eosin and Masson staining, reverse transcription-quantitative polymerase chain reaction, Western blot, and immunofluorescence staining. Additionally, Western blot and chromatin immunoprecipitation were used to test H3K27 acetylation levels and the binding of H3K27ac to galectin-3, respectively. After radiation exposure, heart tissues from the galectin-3 knockout mice had a smaller fibrotic area compared to normal mice, with reduced expression levels of collagen type-I/-III and MMP2/MMP9. SIRT2 was down-regulated and galectin-3 was up-regulated after RIHD treatment. The histone deacetylase inhibitor sirtinol promoted galectin-3 expression and H3K27 acetylation in a time-dependent manner, and increased H3K27ac enrichment in the galectin-3 promoter. Overexpression of SIRT2 down-regulated H3K27ac, collagen type-I/-III, and MMP2/MMP9 expression levels, and reduced the fibrotic area in mouse heart tissues. However, these effects were reversed by the additional overexpression of galectin-3. SIRT2 facilitates deacetylation of H3K27 to inhibit galectin-3 transcription, thus ameliorating RIMF in mice.

Study on the Dynamic Changes of Myocardial Injury Markers in Radiotherapy for Esophageal Carcinoma and Its Correlation with Cardiac Dosimetry

It was hypothesized that radiotherapy for esophageal cancer could cause radiation-induced heart damage. To investigate the dynamic changes of myocardial enzyme, high-sensitive troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide precursors (PRO-BNP) and left ventricular ejection fraction (LVEF) during radiotherapy and six months after radiotherapy for middle and lower thoracic squamous cell carcinoma, and to analyze the correlation between these indicators and dose-volume histogram (DVH) parameters of the heart. A total of 35 patients with thoracic esophageal squamous cell carcinoma who underwent radical concurrent chemoradiotherapy were enrolled in the study. Radiation therapy was performed for up to 6 weeks. All patients received Intensity modulated radiation therapy (IMRT). Total radiation dose was from 50.4Gy to 60 Gy in each patient with a dose of 1.8-2.0 Gy per fraction. Blood samples to determine creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB), lactic dehydrogenase (LDH), alpha-hydroxybutyric dehydrogenase (α-HBDH), hs-TnT, PRO-BNP and LVEF were measured before radiotherapy, during (10th -20th fraction), at the end of radiotherapy, 1, 3, 6 months after radiotherapy. The dynamic changes of the above indexes were analyzed. The correlation between the above indexes and the mean heart dose (Dmean), V5-V60 (dose-volume histograms data were recorded in discrete 5Gy dose levels) of the heart in the course of radiotherapy was also analyzed. The Serum hs-TNT and LVEF show an upward trend during radiotherapy, at the end of radiotherapy and 6 months after radiotherapy for esophageal cancer. The hs-TnT of patients before, during, at the end of radiotherapy and 1, 3, and 6 months after radiotherapy were 7.2pg/ml, 9.1pg/ml, 9.1pg/ml, 9.0pg/ml, 9.4pg/ml, and 8.1pg/ml, respectively (p<0.05). The LVEF were 63.7%, 62.4%, 62.0%, 62.5%, 62.2%, 61.9% respectively (p<0.05). The pro-BNP showed an upward trend during radiotherapy and gradually returned to normal after radiotherapy. The CK and CK-MB showed a downward trend during radiotherapy and 1 month after radiotherapy, and gradually returned to normal 3 months after radiotherapy. Compared with the low dose group (the average dose of heart < 2000cGy), the high dose group (≥2000cGy) had a greater increase in hs-TNT, pro-BNP and LVEF, and a slower recovery time. There was no correlation between the changes of myocardial enzyme, hs-TnT, PRO-BNP, LVEF and the heart mean dose, V5-V60 during radiotherapy (p>0.05). Cardiac injury induced by concurrent chemoradiotherapy for middle and lower thoracic esophageal cancer can lead to the increase of serum hs-TNT and pro-BNP and the increase of LVEF in the early stage of treatment, and this phenomenon is more obvious in the high-dose group. The hs-TnT and PRO-BNP are sensitive parameters to reflect the heart damage in esophageal cancer radiotherapy, which may provide reference for the heart protection during radiotherapy.

Oncostatin M/Oncostatin M Receptor Signal Induces Radiation-Induced Heart Fibrosis by Regulating SMAD4 in Fibroblast

Radiation-induced heart fibrosis (RIHF) is a severe consequence of radiation-induced heart damage (RIHD) leading to impaired cardiac function. The involvement of oncostatin M (OSM) and its receptor (OSMR) in RIHD remains unclear. This study aimed to investigate the specific mechanism of OSM/OSMR in RIHF/RIHD. RNA sequencing was performed on heart tissues from a RIHD mouse model. OSM levels were assessed in serum samples obtained from patients receiving thoracic radiation therapy (RT), as well as in RIHF mouse heart tissues and serum using enzyme-linked immunosorbent assay. Fiber activation was evaluated through costimulation of primary cardiac fibroblasts and NIH3T3 cells with RT and OSM, using Western blotting, immunofluorescence, and quantitative Polymerase Chain Reaction (qPCR). Adeno-associated virus serotype 9-mediated overexpression or silencing of OSM specifically in the heart was performed in vivo to assess cardiac fibrosis levels by transthoracic echocardiography and pathologic examination. The regulatory mechanism of OSM on the transcription level of SMAD4 was further explored in vitro using mass spectrometric analysis, chromatin immunoprecipitation-qPCR, and DNA pull-down. OSM levels were elevated in the serum of patients after thoracic RT as well as in RIHF mouse cardiac endothelial cells and mouse serum. The OSM rate (post-RT/pre-RT) and the heart exposure dose in RT patients showed a positive correlation. Silencing OSMR in RIHF mice reduced fibrosis, while OSMR overexpression increased fibrotic responses. Furthermore, increased OSM promoted histone acetylation (H3K27ac) in the SMAD4 promoter region, influencing SMAD4 transcription and subsequently enhancing fibrotic response. The findings demonstrated that OSM/OSMR signaling promotes SMAD4 transcription in cardiac fibroblasts through H3K27 hyperacetylation, thereby promoting radiation-induced cardiac fibrosis and manifestations of RIHD.

Early and Accurate Detection of Radiation-induced Heart Damage by Cardiodynamicsgram.

Cardiodynamicsgram (CDG) has emerged recently as a noninvasive spatiotemporal electrocardiographic method for subtle cardiac dynamics information analysis within electrocardiogram (ECG). This study explored the feasibility of CDG for detecting radiation-induced heart damage (RIHD) in a rat model. A single radiation dose of 40Gy was delivered to the cardiac apex of female Wistar rats. First, CDG was generated through dynamic modeling of ECG signals using the deterministic learning algorithm. Furthermore, CDG indexes were calculated using the wavelet transform and entropy. In this model, CDG entropy indexes decreased significantly after radiotherapy. The shape of CDG changed significantly after radiotherapy (irregular shape) compared with controls (regular shape). Macrophage and fibrosis in myocardium of rats increased significantly after radiotherapy. CDG changes after radiotherapy were significantly correlated with histopathological changes and occurred significantly earlier than histopathological changes. This study provides an experimental basis for the clinical application of CDG for the early detection of RIHD.

Acetylation of Atp5f1c Mediates Cardiomyocyte Senescence via Metabolic Dysfunction in Radiation-Induced Heart Damage.

Objective Ionizing radiation (IR) causes cardiac senescence, which eventually manifests as radiation-induced heart damage (RIHD). This study is aimed at exploring the mechanisms underlying IR-induced senescence using acetylation proteomics. Methods Irradiated mouse hearts and H9C2 cells were harvested for senescence detection. Acetylation proteomics was used to investigate alterations in lysine acetylation. Atp5f1c acetylation after IR was verified using coimmunoprecipitation (Co-IP). Atp5f1c lysine 55 site acetylation (Atp5f1c K55-Ac) point mutation plasmids were used to evaluate the influence of Atp5f1c K55-Ac on energy metabolism and cellular senescence. Deacetylation inhibitors, plasmids, and siRNA transfection were used to determine the mechanism of Atp5f1c K55-Ac regulation. Results The mice showed cardiomyocyte and cardiac aging phenotypes after IR. We identified 90 lysine acetylation sites from 70 protein alterations in the heart in response to IR. Hyperacetylated proteins are primarily involved in energy metabolism. Among them, Atp5f1c was hyperacetylated, as confirmed by Co-IP. Atp5f1c K55-Ac decreased ATP enzyme activity and synthesis. Atp5f1c K55 acetylation induced cardiomyocyte senescence, and Sirt4 and Sirt5 regulated Atp5f1c K55 deacetylation. Conclusion Our findings reveal a mechanism of RIHD through which Atp5f1c K55-Ac leads to cardiac aging and Sirt4 or Sirt5 modulates Atp5f1c acetylation. Therefore, the regulation of Atp5f1c K55-Ac might be a potential target for the treatment of RIHD.

Effectiveness of Proanthocyanidin plus Trimetazidine in the Treatment of Non-Small-Cell Lung Cancer with Radiation Heart Injury.

This study was intended to explore the effect of proanthocyanidin (PC) combined with trimetazidine in non-small-cell lung cancer (NSCLC) with radiation-induced heart damage (RIHD). It was a prospective randomized controlled study that 86 NSCLC patients with radiation treatment in Cangzhou People's Hospital from January 2019 and June 2021 were enrolled and randomized to either the control group or the study group via the random table method, 43 cases in each group. The control group received trimetazidine, and the study group additionally received PC. The incidence of RIHD-related clinical manifestation, RIHD-related ECG, and RIHD-related cardiac ultrasound change were all lower in the study group. After radiotherapy, the serum level of superoxide dismutase (SOD) was higher, and malondialdehyde (MDA) was lower in the study group when compared with the control group. After radiotherapy, the serum levels of brain natriuretic peptide (BNP), cardiac troponin (cTnT), creatine kinase (CK), and creatine kinase isoenzymes (CKMB) were all lower in the study group when compared with the control group. The efficacy of PC plus trimetazidine for NSCLC with RIHD is superior to trimetazidine alone, and it significantly mitigates radiation-induced inflammatory response and oxidative stress.

Pyrrolidine Dithiocarbamate Might Mitigate Radiation-Induced Heart Damage at an Early Stage in Rats.

Objective: Radiation-induced heart damage (RIHD) is becoming an increasing concern due to offsetting clinical benefits of radiotherapy to a certain extent. Pyrrolidine dithiocarbamate (PDTC) as an antioxidant has been implicated in cardioprotective effects. We aimed to investigate whether pyrrolidine dithiocarbamate could attenuate heart damage at an early stage post-irradiation and unveil the potential mechanisms. Methods: A total of 15 adult male Sprague–Dawley rats were randomized into the control, irradiation (IR), and PDTC plus irradiation (PDTC + IR) groups. Hearts were irradiated with a single fraction of 20.0 Gy. Rats received daily intraperitoneal injection of PDTC for 14 days. At the 14th day post-irradiation, echocardiography was performed, and rats were killed. Morphological damage was examined by hematoxylin–eosin (HE) stain and Masson’s trichrome stain. The collagen volume fraction (CVF) was applied for semi-quantitative analysis. The protein levels were analyzed by Western blot and mRNA levels by quantitative real-time PCR. Results: No significant damage to systolic function of left ventricular was induced at an early stage post-irradiation. HE staining of cardiac tissue showed that the disordered arrangement of myocardial cells and abnormal cell infiltration were alleviated in the PDTC + IR group. The increased CVF in the irradiation group was inhibited in the PDTC + IR group (22.05 ± 2.64% vs. 9.99 ± 1.65%, p < 0.05). The protein levels of nuclear factor-kappa B (NF-κB), hypoxia-inducible factor-1α (HIF-1α), and COL-1 were downregulated after treatment with PDTC (p < 0.05), and there was a declining trend in the protein of the connective tissue growth factor (CTGF). The mRNA expression of NF-κB and HIF-1α in the PDTC plus irradiation group was lower than that in the irradiation group (p < 0.05), and there was a declining trend in the mRNA expression of the connective tissue growth factor and COL-1. Conclusion: PDTC alleviates myocardial cell disordered arrangement, abnormal cell infiltration, and pro-fibrotic change at an early stage in rats with radiation-induced heart damage. Such a protective effect is closely associated with the downregulation of NF-κB.

Two-dimensional speckle tracking echocardiography in evaluating radiation-induced heart damage

ObjectiveRadiation-induced heart damage (RIHD) in malignant tumor patients with thoracic radiotherapy has been well documented. However, there is no study on the cardiac toxicity of stereotactic body radiotherapy (SBRT) based on two-dimensional speckle tracking echocardiography (2D STE). MethodsIn a prospective cohort trial, 48 patients with malignant tumor (including patients with lung cancer, pulmonary metastases and other tumor) were assigned to receive thoracic SBRT. Circulating biomarkers, electrocardiogram (ECG), echocardiography, and 2D STE were performed prior to and within two months after thoracic radiotherapy. The primary outcome of the trial was a decrease in global longitudinal strain (GLS) ≥ 10%. The secondary outcomes were major adverse cardiovascular events (MACE). Analysis were conducted using paired sample t-test, Wilcoxon signed rank test and Chi square test. ResultsThe morbidity of RIHD is 44% within 2 months after SBRT in malignant tumor patients. Compared with pre-RT, a significant decrease in GLS was observed post-RT (−17.98 ​± ​3.54% vs. −16.92 ​± ​3.41%; P ​= ​0.008), without any significant change in left ventricular ejection fraction (LVEF) (68.54 ​± ​6.06 vs. 69.63 ​± ​4.45; P ​= ​0.234), left ventricular mass (LVM) (P ​= ​0.342), ECG parameters, creatine kinase (P ​= ​0.074), cardiac troponin T (P ​= ​0.829) or N-terminal pro-B-type natriuretic peptide (P ​= ​0.453) at during the post-RT period. There was no evidence that RIHD was correlated with age (P ​= ​1.000), mean heart dose (P ​= ​0.602), BED (P ​= ​0.234), EQD2/2 (P ​= ​0.615), V5 (P ​= ​0.506), V10 (P ​= ​0.578), V20 (P ​= ​0.670) and V30 (P ​= ​0.741). Subgroup analysis showed, there is still a significant decline of GLS (−18.30 ​± ​3.79% vs. −17.11 ​± ​3.58%; P ​= ​0.018) in patients without anthracycline treatment. And the decrease of GLS (−19.14 ​± ​2.42% vs. −16.85 ​± ​2.46%; P ​= ​0.004) was more significantly post-RT in anthracycline treatment group. MACE were found in one patient over a period of two months after SBRT. ConclusionsBy using strain analysis subclinical cardiac dysfunction was found to be evident early after SBRT, despite unchanged conventional indices such as LVEF, ECG parameters or circulating biomarkers. And the decrease of GLS is still existed after the effect of anthracycline was removed. Trial registrationClinicalTrials.gov, registration number: NCT04443400.

Study on the Mechanism of Autophagy in Rats With Radiation Induced Heart Damage at Different Time Points

It is an important mode to combine local radiotherapy with systemic targeted therapy against tumor. MTOR is an ideal choice for tumor targeted therapy, which has been identified in the cardiovascular disease. Endoplasmic reticulum stress (ERS) was involved in the process of radiation induced heart damage (RIHD) in previous study, which could trigger autophagy by inhibiting mTOR. Here we established an animal experimental model to observe the performance of RIHD at different time points, and explored the mechanism of autophagy in a rat model of RIHD.56 adult male SD rats were randomly divided into four groups (n = 14): Control group (A), Radiation group (B), Rapamycin+radiation group (C), 3-MA + radiation Group (D). Animal echocardiography was performed on the 14th and 28th days after irradiation to record left ventricular function. Levels of IL-4, TNF-α, TGF-β1 and Beclin-1 and LC3 related to autophagy were assessed by quantitative analysis of protein expression.1. On the 14th day after irradiation, radiation exposure caused a decrease in LVFS, and the decrease was recovered in D group but was not changed in C group. On the 28th day after irradiation, radiation exposure caused an increase in LVEF and LVFS, accompanied by LVAW; s thickening, and except for the decrease of LVAW; s in C group there was no change of the other parameters in C and D group compared with B group. 2. On the 14th day after the heart of the rat is irradiated, edema of myocardial cells and apoptosis increased, myocardial interstitial and perivascular inflammation cells infiltrated, and myocardial interstitial collagen deposition increased. The above-mentioned injuries were aggravated in C group and were alleviated in D group compared with B group. With time extending to 28 days after irradiation, the above-mentioned histopathological changes were progressively exacerbated. Different from changes of the 14th day, these damages were alleviated in C group and were aggravated in D group on the 28th day. 3. On the 14th day, irradiation increased the levels of autophagy-related proteins Beclin-1 and LC3, inflammatory factors IL-4, TNF-α and TGF-β1. Enhancing autophagy furtherly increased the levels of inflammatory factors IL-4, TNF-α and TGF-β1. On the 28th day, irradiation reduced the expression of Beclin-1 and LC3 but still increased the levels of IL-4, TNF-α and TGF-β1. Enhancing autophagy decreased the levels of inflammatory factors IL-4, TNF-α and TGF-β1.RIHD were progressively exacerbated with the extension of observation time. Autophagy may play a bidirectional regulatory role in radiation- induced cardiac injury, and the mechanism of action is different at different time points. On the 14th day after irradiation, activated autophagy exacerbated acute radiation heart injury to a certain extent. As time prolonged to 28 days after irradiation, down-regulated autophagy exacerbated acute radiation heart injury to a certain extent.

Study on Damage of Myocardial Tissue Under Low-Dose Heart Irradiation in Rats

<h3>Purpose/Objective(s)</h3> Radiation induced heart damage (RIHD) is an important late toxicity of thoracic radiotherapy, which is closely relating with the fractional dose of radiotherapy. With the wide application of stereotactic body radiotherapy and hyperfractionated radiotherapy, the single dose and biological equivalent dose (BED) of the heart of exposure have increased when comparing with conventionally fractionated radiotherapy. However, the mean cardiac dose (MHD), which is frequently used clinically to ensure the control of cardiac damage, is continuously decreased to 26 Gy, 20 Gy, etc. There is still controversy about how much dose could control heart radiation damage better. In this study, 15 Gy/3f low-dose irradiation of the whole heart of rats, which BED is similar with 24 Gy/12f irradiation, is selected to explore the possibility and characteristics of RIHD occurrence, and explore the effect of combined recombinant human endostatin on myocardial damage. <h3>Materials/Methods</h3> 75 SD adult male rats were randomly divided into control (C group, E group, MHD₂₅ group) and experimental group (MHD₁₅ group, MHD_15+E group). The irradiation method was single dose 5 Gy/f, once per day, continuous irradiation 3d or 5d. After the irradiation, the E group and MHD_15+E group were given recombinant human endostatin 6mg/kg intraperitoneal injection, once per day, for 14 consecutive days. At 1, 3, and 6 months after intervention, 5 rats in each group were randomly selected for HE, Masson, and immunohistochemical CD34 microvessel staining, and Western Blot detected mitochondrial Complex II protein expression. Two-way ANOVA statistics. <h3>Results</h3> Compared with C group, edema and disorder of myocardial cells, infiltration of inflammatory cells and decrease of microvessel density was observed at 1 month after intervention in HE staining in MHD₁₅ and MHD_15+E group. The expression of complex II protein decreased at 6 months, and the degree of decrease was less than that in MHD₂₅ group (positive control group) (<i>P</i> < 0.05). The microvessel density was further decreased compared with 1 month. Myocardial fibrosis induced by 15 Gy/3f low-dose irradiation of SD rat heart mainly occurred at 6 months, which observed myocardial cord or reticular fibrosis and collagen deposition. Semi-quantitative analysis of myocardial collagen volume fraction CVF significantly increased (<i>P</i> < 0.001) in HE and Masson staining. Details is shown in the table below. Compared with C group, E group observed myocardial edema and decreased microvessel density. There was no significant difference between MHD₁₅ and MHD_15+E group. <h3>Conclusion</h3> Low dose irradiation of 15 Gy/3f (BED = 40 Gy) still cause myocardial fibrosis and damage of cardiac function in SD rats. RIHD were observed after 6 months, which was equal to about 1/5 of the rat's life span, and the time was delayed when compared with the time of RIHD caused by high dose irradiation. Cardiotoxicity was not increased significantly combining recombinant human endostatin on the basis of low-dose cardiac.

Mechanism and Functional Parameter of Myocardial Damage Induced by Low-Dose Radiation in Rats

Radiation induced heart damage (RIHD) is the leading cause of non-cancer-related deaths in patients receiving thoracic radiotherapy. The mean cardiac dose (MHD) of normal tissue tolerance in NCCN guidelines for radiotherapy has been continuously decreased from 35 Gy in 2017 to 2020 20 Gy, indicating there is controversy of MHD that how much dose could control cardiac radiation damage better. In this study, 15 Gy/3f (BED = 40 Gy) low-dose irradiation of SD rat heart was used to explore the mechanism and functional parameter changes of RIDH caused by low-dose irradiation, and to explore the effect of combining recombinant human endostatin (E).75 SD adult male rats were randomly divided into control group (C, E, MHD25) and experimental group (MHD15, MHD15+E). A single dose 5 Gy/f, once per day, continuous irradiation 3d or 5d. After the irradiation, the E group and MHD15+E group were given recombinant human endostatin 6mg/kg intraperitoneal injection, once per day, for 14 consecutive days. At 24h, 48h and 15d after the intervention, the blood of the rats was taken to measure CK, CK-MB, LDH and CRP. At 1, 3 and 6 months, 5 rats after cardiac echocardiography was performed in each group were randomly killed and myocardial tissues were collected for Masson staining, Western Blot and qPCR. Two-way ANOVA statistics.There was no difference in LDH, CK, CK-MB, and CRP in the same time period among the groups at 24h, 48h, and 14d after intervention (P > 0. 05). Compared with group C, the EF and FS of the MHD25, MHD15 and MHD15+E group all decreased at 3 months (P < 0.05), and the degree was similar (P > 0.05). The EF and FS of the MHD25, MHD15 and MHD15+E group also decreased at 6 months (P < 0.05), and the degree was similar (P > 0.05). Comparing 6 months with 1 month, EF and FS of each group decreased (P < 0.01). Myocardial fibrosis MHD25 group appeared after 3 months of irradiation. Myocardial collagen volume fraction (CVF) increased (P < 0.05), and TGF-β1, P-smad2, Collagen-I protein expression increased (P < 0.05), and TGF-β1, Smad, Collagen-I gene expression increased (P < 0.05). The MHD15 and MHD15+E group showed the above changes at 6 months, and the degree of increase of the above-mentioned protein and gene expression was lower than that of the MHD25 group (P < 0.05). The expressions of the above-mentioned proteins and genes in the MHD15+E group were higher than those in the MHD15 group (P < 0.05). The protein level of Smad2 was similar in each group (P > 0.05).SD rat heart 15 Gy/3f (BED = 40 Gy) low-dose irradiation cause cardiac function damage in the early stage and myocardial fibrosis in the late stage, the appearance delayed and degree is lower than that of high-dose irradiation. On the basis of low-dose irradiation, combined with recombinant human endostatin increase the expression of related factors of TGF-β/Smad signaling pathway. Echocardiography may be able to predict the occurrence of RIDH early, but serological predictive indicators have yet to be found.

Radiation‑induced dysfunction of energy metabolism in the heart results in the fibrosis of cardiac tissues.

Thoracic radiotherapy increases the risk of radiation-induced heart damage (RIHD); however, the molecular mechanisms underlying these changes are not fully understood. The aim of the present study was to investigate the effects of radiation on the mouse heart using high-throughput proteomics. Male C57BL/6J mice were used to establish a model of RIHD by exposing the entire heart to 16 Gy high-energy X-rays, and cardiac injuries were verified using a cardiac echocardiogram, as well as by measuring serum brain natriuretic peptide levels and conducting H&E and Masson staining 5 months after irradiation. Proteomics experiments were performed using the heart apex of 5-month irradiated mice and control mice that underwent sham-irradiation. The most significantly differentially expressed proteins were enriched in ‘cardiac fibrosis’ and ‘energy metabolism’. Next, the cardiac fibrosis and changes to energy metabolism were confirmed using immunohistochemistry staining and western blotting. Extracellular matrix proteins, such as collagen type 1 α 1 chain, collagen type III α 1 chain, vimentin and CCCTC-binding factor, along with metabolism-related proteins, such as fatty acid synthase and solute carrier family 25 member 1, exhibited upregulated expression following exposure to ionizing radiation. Additionally, the myocardial mitochondria inner membranes were injured, along with a decrease in ATP levels and the accumulation of lactic acid in the irradiated heart tissues. These results suggest that the high doses of ionizing radiation used lead to structural remodeling, functional injury and fibrotic alterations in the mouse heart. Radiation-induced mitochondrial damage and metabolic alterations of the cardiac tissue may thus be a pathogenic mechanism of RIHD.

Ultrafiltration Extract of Radix Angelica Sinensis and Radix Hedysari Attenuates Risk of Low-Dose X-Ray Radiation-Induced Myocardial Fibrosis In Vitro.

The risk of radiation-induced heart damage (RIHD) is a growing concern since recent advances in radiation therapy (RT) for cancer treatments have significantly improved the number of survivors. Radiation-induced myocardial fibrosis (RIMF) is the final pathological condition of RIHD and main change leading to serious cardiovascular complications following RT. The aim of this study was to investigate the effect of ultrafiltration extract of Radix Angelica Sinensis and Radix Hedysari (RAS-RH) on the proliferation, apoptosis, and reactive oxygen species (ROS) of cardiac fibroblasts after X-irradiation in vitro. The RAS-RH extract was from the Danggui Buxue decoction (DBD) in TCM. Primary cardiac fibroblasts were irradiated with 1 Gy X-ray to evaluate the effect of RAS-RH on the expression levels of cell proliferation, apoptosis, ROS, and fibrotic molecules. Our data demonstrated that X-irradiation at 1 Gy resulted in the proliferation of cardiac fibroblasts; RAS-RH attenuated the myocardial fibrosis. Furthermore, X-ray radiation reduced the apoptosis of cardiac fibroblasts; RAS-RH accelerated the apoptosis of these cells after irradiation. In addition, the damage driven by ROS in primary cardiac fibroblasts after irradiation was weakened by RAS-RH and the expression of TGF-β1, Col1, and α-SMA increased after irradiation; RAS-RH decreased the expression of these makers. Overall, these data indicate that low-dose X-ray irradiation boosts myocardial fibrosis, and the effect of RAS-RH protects against fibrosis via attenuating the proliferation and accelerating the apoptosis of myocardial fibroblasts after X-irradiation.

The Role of Mitochondrial Dysfunction in Radiation-Induced Heart Disease: From Bench to Bedside.

Radiation is a key modality in the treatment of many cancers; however, it can also affect normal tissues adjacent to the tumor, leading to toxic effects. Radiation to the thoracic region, such as that received as part of treatment for breast and lung cancer, can result in incidental dose to the heart, leading to cardiac dysfunction, such as pericarditis, coronary artery disease, ischemic heart disease, conduction defects, and valvular dysfunction. The underlying mechanisms for these morbidities are currently being studied but are not entirely understood. There has been increasing focus on the role of radiation-induced mitochondrial dysfunction and the ensuing impact on various cardiac functions in both preclinical models and in humans. Cardiomyocyte mitochondria are critical to cardiac function, and mitochondria make up a substantial part of a cardiomyocyte's volume. Mitochondrial dysfunction can also alter other cell types in the heart. This review summarizes several factors related to radiation-induced mitochondrial dysfunction in cardiomyocytes and endothelial cells. These factors include mitochondrial DNA mutations, oxidative stress, alterations in various mitochondrial function-related transcription factors, and apoptosis. Through improved understanding of mitochondria-dependent mechanisms of radiation-induced heart dysfunction, potential therapeutic targets can be developed to assist in prevention and treatment of radiation-induced heart damage.

Research progress on radiation-induced heart damage—basic mechanism

At present, 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. The incidence of radiation-induced cardiac adverse events can affect the long-term survival of patients. In this article, the recent progress on the basic research of radiation-induced heart damage was described as follows. Key words: Radiation-induced heart damage; Research progress

A Multi-Center Randomized Trial Using Compound Kushen Injection to Decrease Chemoradiotherapy Induced Thoracic Toxicities in Patients with Locally Advanced Non-Small Cell Lung Cancer

To evaluate whether Kushen injection could decrease chemoradiotherapy induced thoracic toxicities in patients with locally advanced non-small cell lung cancer. A prospective, open, randomized, multi-center study was performed, in which a total of 200 patients were enrolled and randomly 1:1 divided into the experimental group and the control group. The patients in the control group were treated with standard chemoradiotherapy including precise thoracic radiotherapy (60Gy/30fraction/6weeks) plus concurrent platinum-based chemotherapy. The patients in the experimental group were treated with Compound Kushen Injection combined with standard chemoradiotherapy. The incidence of adverse events and their severity after treatment were observed per CTCAE5.0. The adverse event rate, clinical symptoms, quality of life, and side effects were observed and assessed. One hundred and seventy-seven qualified patients were included in statistical analysis. Symptomatic radiation-induced pneumonitis was lower in the experimental group than in the group (3.8% vs 13.1%, P＝0.015). Symptomatic radiation-induced esophagitis showed no significant difference in two groups(1.9% vs 2.1%, P＝1.0). No symptomatic radiation-induced heart damage was observed in two groups. Compound Kushen Injection plays a significant role in alleviating symptomatic radiation-induced pneumonitis when combined with radiotherapy for locally advanced non-small cell lung cancer.

Metformin modulates cardiac endothelial dysfunction, oxidative stress and inflammation in irradiated rats: A new perspective of an antidiabetic drug.

Cardiovascular disease is one of the most pivotal disorders after radiotherapy. The aim of this study investigates the possible protective effect of metformin against gamma radiation-induced heart damage in male rats. Group 1 (control) received saline, group 2 was whole body gamma-irradiated 5Gy, group 3 was orally administered metformin 50mg/kg/day for 2weeks, group 4 received metformin 50mg/kg/day for 1week, then exposed to whole-body gamma radiation at a dose of 5Gy and continued with metformin for further 1week. The results revealed that the administration of metformin to irradiated rats significantly ameliorated the changes in cardiac biomarkers (LDH and CK-MB) compared with irradiated group. Heart catalase and SOD activities showed normal level when compared with the irradiated group. Also, NF-κB, IL-6 and TNF- α levels were markedly decreased compared with the corresponding values of irradiated group. Consequently, metformin reduced E-selectin as well ICAM and VCAM-1. These results confirmed by histopathological examination. In conclusion, concomitant administration of metformin during radiotherapy acts as a potent heart protector from oxidative stress, inflammatory mediators and endothelial dysfunction induced damages. Results thus hold a great promise for a new implication of an antidiabetic drug (metformin) as adjunct to radiotherapy.

Huangqi Shengmai Yin Protects against Radiation-Induced Cardiac Fibrosis Injury by Regulating the TGF-β1/Smads and MMPs.

Background Radiation-induced heart damage is considered to be a progressive process of fibrosis. Emerging evidence has indicated that the Smads and matrix metalloproteinases (MMPs)/tissue inhibitors of MMPs (TIMP) may be involved in radiation-induced cardiac fibrosis (RICF) by regulating the activation of TGF-β1 signaling pathway. Based on this, the present study was undertaken to characterize the effect of Huangqi Shengmai Yin (HSY) on RICF in a rat model. Methods Precardiac region of rats was irradiated with 25 Gy X-rays, and their myocardial pathology scores in terms of injury and collagen volume fraction (CVF) and the expression levels of fibrotic molecules were detected. Results The pathology scores and CVF in myocardial tissue increased after irradiation, and the expression of TGF-β1, Col1, and Col3 increased. This change indicated that such irradiation promoted the fibrosis damage in rat hearts. The damage was accompanied by an increase in the expression of Smad 2, Smad3, Smad4, and MMP14 and a decrease in the expression of Smad 7 and TIMP1. Administration of HSY weakened the RICF by decreasing pathology score and CVF and decreased the expression of TGF-β1, Col1, and Col3 in irradiated rat hearts. In addition, Smad2, Smad3, Smad4, and MMP14 were downregulated, while Smad 7 and TIMP1 were upregulated during intervention with HSY. Conclusions The involvement of the TGF-β1/Smads and MMPs/TIMP system in RICF was confirmed. This study demonstrated, for the first time, that HSY attenuates the effects of RICF in a rat model. The effect HSY was found to be closely related to the TGF-β1/Smads signaling pathway and MMPs system. These results suggest that HSY is a prospective drug for clinical treatment of RICF.