Radiation-induced Heart Disease 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.

The impact of X-rays on cardiac hydrometabolism and the regulatory role of AS-IV

BackgroundRadiation-induced cardiac injury has emerged as a significant pathological entity, with many studies focusing on the fibrotic changes in myocardial tissue. However, these do not offer solutions for the clinical prevention and treatment of radiation-induced heart disease. Regulating hydrometabolism presents a potential therapeutic target for the management of cardiovascular diseases. This research seeks to explore the impacts of irradiation on cardiac hydrometabolism and its regulatory mechanisms. MethodsThe impact of X-ray radiation on cardiac and cardiomyocyte hydrometabolism was studied through in vivo and in vitro experiments, examining the pharmacological effects and mechanisms of PX-478 and AS-IV interventions in cardiomyocytes. Results28 days after direct chest irradiation with 20 Gy X-rays, C57BL/6 mice exhibited an increased heart wet-to-dry weight ratio, significant enlargement of cardiomyocyte cross-sectional area, and elevated protein expression of HIF-1α, AQP1, AQP4, Cx43, Caspase3, and Bax, with decreased expression of Bcl-2. Irradiation with 6 Gy X-rays induced edema and damage in AC16 and HL-1 cardiomyocytes at 24, 48, and 72 h, with increased expression of HIF-1α, AQP1, AQP4, and Cx43 proteins post-radiation. Inhibition of HIF-1α ameliorated edema and apoptosis in AC16 and HL-1 cardiomyocytes, reducing the expression of HIF-1α, AQP1, AQP4, and Cx43 proteins. AS-IV demonstrated strong binding affinity with HIF-1α, and successfully attenuated the expression levels of HIF-1α, AQP1, AQP4, and Cx43 proteins, alleviating edema, mitochondrial swelling, and apoptosis in AC16 and HL-1 cardiomyocytes. Furthermore, AS-IV improved cardiomyocyte edema by restoring the activity of Na/K-ATPase. ConclusionAberrant activation of the HIF-1α/AQPs/Cx43 axis is a key mechanism in X-ray-induced cardiomyocyte edema and damage. AS-IV can ameliorate X-ray induced cardiac damage by regulating hydrometabolism.

Recent radiotherapy could reduce heart-related death in patients with esophageal cancer: SEER database analysis

BackgroundThere have been several reports showing that heart-related deaths are common in long-term survivors of esophageal cancer after radiation therapy; however, radiotherapy technology is evolving year by year. This study was carried out using the SEER database to determine whether the frequency of mortality from heart disease after radiotherapy has improved over time in patients with esophageal cancer.MethodsSEER*Stat statistical software version 8.3.9.2 (National Cancer Institute) was used to perform case listing and data extraction. We reviewed causes of death in 8,297 patients who were treated by radiotherapy without surgery between 2004 and 2015 (radiotherapy group). For comparison with this group, we also reviewed causes of death in 5,149 patients who were treated by surgery without radiotherapy (surgery group).ResultsIn the radiotherapy group, the cumulative heart-related death rate in patients with carcinoma in the middle to abdominal esophagus, for which it was considered that the heart was irradiated with a higher dose, was significantly higher than that in patients with carcinoma in the cervical to upper thoracic esophagus (p = 0.017). However, in the surgery group, the cumulative heart-related death rate in patients with carcinoma in the middle to abdominal esophagus tended to be lower than that in patients with carcinoma in the cervical to upper thoracic esophagus (p = 0.063). The cumulative heart-related death rate in patients treated in 2010–2015 was significantly lower than that in patients treated in 2004–2009 in the radiotherapy group (p = 0.011), although the cumulative heart-related death rate was not significantly different between patients treated in 2010–2015 and patients treated in 2004–2009 in the surgery group (p = 0.90).ConclusionsThe results suggest that recent advances in radiotherapy have enabled a reduction in radiation-induced heart disease in patients with esophageal cancer.

Outcomes of Surgical Valve Replacements for Radiation-Induced Valvulopathy

Objective(s)Cancer patients who receive radiation therapy to the thorax often develop radiation-induced heart disease (RIHD) decades later. Prior chest radiation is associated with elevated perioperative risk of complications and mortality following cardiac surgery. Whether the type of valve (mechanical vs. bioprosthetic) used affects outcomes in patients with RIHD is unknown. MethodsThis retrospective review analyzed the characteristics and post-operative outcomes of patients with a prior history of chest radiation for Hodgkin or non-Hodgkin lymphoma who underwent surgical valve replacement at a single institution between 2000 and 2021. Both 30-day peri-operative outcomes and long-term survival were assessed. ResultsMechanical valve patients tended to be younger, have more valves replaced, and have undergone prior coronary artery bypass grafting (CABG) than bioprosthetic valve recipients. Valve type alone did not alter perioperative complications or overall survival. Median survival was 11.0 years in mechanical and 10.9 years in bioprosthetic valve patients (P = 0.930). Twelve patients underwent valve reinterventions (6 mechanical, 6 bioprosthetic), and three underwent transplant. Single valve (AV or MV) recipients fared better with median survival of 13.3 years compared to 6.2 years in those who underwent combined AVR+MVR (P<0.0001). ConclusionsPatients with RIHD who undergo surgical valve replacement have similarly suboptimal short- and long-term outcomes regardless of mechanical vs. bioprosthetic valve type. Those who required combined aortic and mitral valve replacement had especially high 10-year overall mortality. Further investigation in a larger dataset including transcatheter approaches is warranted.

Cardiac Conduction System as an OAR in Radiation Therapy: Doses to SA/AV Nodes and Their Reduction

PurposeDespite advancements in radiation techniques, concerns persist regarding the adverse effects of radiation therapy, particularly cardiotoxicity or radiation-induced heart disease. Recently, arrhythmogenic toxicity has come to the forefront—the impact of radiation therapy on the cardiac conduction system. Our objective was to conduct a dosimetric study and subsequently investigate the feasibility of optimizing the sinoatrial (SA) and atrioventricular (AV) nodes as organs at risk (OARs) in proton radiation therapy for non–small cell lung cancer with N3 disease. Patients and MethodsThirty-two non–small cell lung cancer patients with N3 disease undergoing proton radiation therapy were included. Sinoatrial and AV nodes, along with standard OARs, were delineated. Dosimetric analysis and optimization were performed using intensity-modulated proton therapy. ResultsPatients surpassing a predefined SA node dose threshold underwent dose optimization. Proton radiation therapy with pencil beam scanning demonstrated a significant reduction in SA and AV node doses without compromising target volume coverage or significant shift in the dose to other monitored OARs. ConclusionDose reduction to the SA and AV nodes for pencil beam scanning is a relatively simple task, and the reduction can be very substantial. Larger cohort studies and diverse radiotherapeutic modalities are needed for further validation and refinement of dose constraints.

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.

EEPD1 attenuates radiation-induced cardiac hypertrophy and apoptosis by degrading FOXO3A in cardiomyocytes.

Radiation-induced heart disease (RIHD) is a severe delayed complication of thoracic irradiation (IR). Endonuclease/exonuclease/phosphatase family domain-containing 1 ( EEPD1) plays an important role in DNA damage repair, but its role in RIHD is less known. In this study, EEPD1 global knockout mice, C57BL/6J mice, and C57BL/6J mice overexpressing EEPD1 are treated with radiation at a total dose of 20 Gy or 0 Gy. After 9 weeks, echocardiography is used to assess cardiac hypertrophy and apoptosis. The results show that EEPD1 deletion exacerbates radiation-induced cardiac hypertrophy and apoptosis, while EEPD1 overexpression has the opposite effect. Further mechanistic investigations reveal that EEPD1 interacts with FOXO3A and destabilizes it by catalyzing its deubiquitination. Inhibition of FOXO3A ameliorates cardiac hypertrophy and apoptosis after EEPD1 knockdown. Thus, EEPD1 protects against radiation-induced cardiac hypertrophy and apoptosis via destabilization of FOXO3A, which may offer new insight into therapeutic strategies for RIHD.

The potential treatment of N-acetylcysteine as an antioxidant in the radiation-induced heart disease.

Radiation-induced heart disease (RIHD) is a serious complication of thoracic tumor radiotherapy that substantially affects the quality of life of cancer patients. Oxidative stress plays a pivotal role in the occurrence and progression of RIHD, which prompted our investigation of an innovative approach for treating RIHD using antioxidant therapy. We used 8-week-old male Sprague-Dawley (SD) rats as experimental animals and H9C2 cells as experimental cells. N-acetylcysteine (NAC) was used as an antioxidant to treat H9C2 cells after X-ray irradiation in this study. In the present study, the extent of cardiomyocyte damage caused by X-ray exposure was determined, alterations in oxidation/antioxidation levels were assessed, and changes in the expression of genes related to mitochondria were examined. The degree of myocardial tissue and cell injury was also determined. Dihydroethidium (DHE) staining, reactive oxygen species (ROS) assays, and glutathione (GSH) and manganese superoxide dismutase (Mn-SOD) assays were used to assess cell oxidation/antioxidation. Flow cytometry was used to determine the mitochondrial membrane potential and mitochondrial permeability transition pore (mPTP) opening. High-throughput transcriptome sequencing and bioinformatics analysis were used to elucidate the expression of mitochondria-related genes in myocardial tissue induced by X-ray exposure. Polymerase chain reaction (PCR) was used to verify the expression of differentially expressed genes. X-ray irradiation damaged myocardial tissue and cells, resulting in an imbalance of oxidative and antioxidant substances and mitochondrial damage. NAC treatment increased cell counting kit-8 (CCK-8) levels (P=0.02) and decreased lactate dehydrogenase (LDH) release (P=0.02) in cardiomyocytes. It also reduced the level of ROS (P=0.002) and increased the levels of GSH (P=0.04) and Mn-SOD (P=0.01). The mitochondrial membrane potential was restored (P<0.001), and mPTP opening was inhibited (P<0.001). Transcriptome sequencing and subsequent validation analyses revealed a decrease in the expression of mitochondria-related genes in myocardial tissue induced by X-ray exposure, but antioxidant therapy did not reverse the related DNA damage. Antioxidants mitigated radiation-induced myocardial damage to a certain degree, but these agents did not reverse the associated DNA damage. These findings provide a new direction for future investigations by our research group, including exploring the treatment of RIHD-related DNA damage.

Application of two-dimensional speckle-tracking echocardiography in radiotherapy-related cardiac systolic dysfunction and analysis of its risk factors: a prospective cohort study

BackgroundThe cardiac toxicity of radiotherapy (RT) can affect cancer survival rates over the long term. This has been confirmed in patients with breast cancer and lymphoma. However, there are few studies utilizing the two-dimensional speckle-tracking echocardiography (2D-STE) to evaluate the risk factors affecting radiation induced heart disease (RIHD), and there is a lack of quantitative data. Therefore, we intend to explore the risk factors for RIHD and quantify them using 2D-STE technology.MethodsWe ultimately enrolled 40 patients who received RT for thoracic tumors. For each patient, 2D-STE was completed before, during, and after RT and in the follow up. We analyzed the sensitivity of 2D-STE in predicting RIHD and the relationship between RT parameters and cardiac systolic function decline.ResultsLeft ventricle global longitudinal strain (LVGLS), LVGLS of the endocardium (LVGLS-Endo), LVGLS of the epicardium (LVGLS-Epi), and right ventricle free-wall longitudinal strain (RVFWLS) decreased mid- and post-treatment compared with pre-treatment, whereas traditional parameters such as left ventricular ejection fraction (LVEF), cardiac Tei index (Tei), and peak systolic velocity of the free wall of the tricuspid annulus (s’) did not show any changes. The decreases in the LVGLS and LVGLS-Endo values between post- and pre-treatment and the ratios of the decreases to the baseline values were linearly correlated with mean heart dose (MHD) (all P values < 0.05). The decreases in the LVGLS-Epi values between post- and pre-treatment and the ratios of the decreases to the baseline values were linearly correlated with the percentage of heart volume exposed to 5 Gy or more (V5) (P values < 0.05). The decrease in RVFWLS and the ratio of the decrease to the baseline value were linearly related to MHD and patient age (all P values < 0.05). Endpoint events occurred more frequently in the right side of the heart than in the left side. Patients over 56.5 years of age had a greater probability of developing right-heart endpoint events. The same was true for patients with MHD over 20.2 Gy in both the left and right sides of the heart.Conclusions2D-STE could detect damages to the heart earlier and more sensitively than conventional echocardiography. MHD is an important prognostic parameter for LV systolic function, and V5 may also be an important prognostic parameter. MHD and age are important prognostic parameters for right ventricle systolic function.

Dexmedetomidine ameliorates x-ray-induced myocardial injury via alleviating cardiomyocyte apoptosis and autophagy

BackgroundRadiotherapy is a primary local treatment for tumors, yet it may lead to complications such as radiation-induced heart disease (RIHD). Currently, there is no standardized approach for preventing RIHD. Dexmedetomidine (Dex) is reported to have cardio-protection effects, while its role in radiation-induced myocardial injury is unknown. In the current study, we aimed to evaluate the radioprotective effect of dexmedetomidine in X-ray radiation-treated mice.Methods18 male mice were randomized into 3 groups: control, 16 Gy, and 16 Gy + Dex. The 16 Gy group received a single dose of 16 Gy X-ray radiation. The 16 Gy + Dex group was pretreated with dexmedetomidine (30 µg/kg, intraperitoneal injection) 30 min before X-ray radiation. The control group was treated with saline and did not receive X-ray radiation. Myocardial tissues were collected 16 weeks after X-ray radiation. Hematoxylin-eosin staining was performed for histopathological examination. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was performed to assess the state of apoptotic cells. Immunohistochemistry staining was performed to examine the expression of CD34 molecule and von Willebrand factor. Besides, western blot assay was employed for the detection of apoptosis-related proteins (BCL2 apoptosis regulator and BCL2-associated X) as well as autophagy-related proteins (microtubule-associated protein 1 light chain 3, beclin 1, and sequestosome 1).ResultsThe findings demonstrated that 16 Gy X-ray radiation resulted in significant changes in myocardial tissues, increased myocardial apoptosis, and activated autophagy. Pretreatment with dexmedetomidine significantly protects mice against 16 Gy X-ray radiation-induced myocardial injury by inhibiting apoptosis and autophagy.ConclusionIn summary, our study confirmed the radioprotective effect of dexmedetomidine in mitigating cardiomyocyte apoptosis and autophagy induced by 16 Gy X-ray radiation.

Prevalence and clinical outcomes of acute heart failure among patients with mediastinal radiation exposure: A propensity score matched analysis.

e24029 Background: Radiation therapy (RT) for malignancy in mediastinal region is associated with radiation-induced heart disease in subsequent years, including coronary, valvular, myocardial, pericardial and conduction system disease. Although increased risk of diastolic heart failure (DHF) has been established, there is limited data on the prevalence, trends and outcomes of acute DHF admissions in patients with prior mediastinal RT. Methods: We extracted data from the National Inpatient Sample (NIS) Database from 2016 to 2020. We included all admissions ≥18 years old with a principal diagnosis of acute DHF with and without history of RT for mediastinal cancer using International Classification of Diseases Tenth Revision (ICD-10) codes. Propensity score matching was performed to balance hospital characteristics, patient demographics and comorbidities between the two groups. Univariate logistic regression was performed in the balanced cohorts. The primary outcome was inpatient mortality. Analysis was performed using STATA-MP, version 14.2. Results: A total of 2,356,025 admissions for acute DHF were identified between 2016 to 2020, of which 15,435 (0.65%) had prior mediastinal RT. During the study period, we found an increasing trend in the number of admissions for acute DHF (p trend &lt; 0.01) along with an increased proportion of patients with prior mediastinal RT. (0.55% in 2016 to 0.78% in 2020, p trend &lt; 0.01). After propensity score matching, there was no difference in in-hospital mortality (odds ratio [OR] 1.12, 95% CI 0.79-1.58, p = 0.537), or complications such as cardiogenic shock, respiratory failure, stroke, venous thromboembolism, or acute kidney injury between the two cohorts. There was no difference in length of stay, however, cohort with history of mediastinal RT had higher hospital charges ($26,634 vs $31,511, p &lt; 0.01). Conclusions: Exposure to mediastinal RT represents a minority but growing number of hospital admission with DHF. The mortality and complications of RT associated DHF does not differ significantly from those with traditional etiologies of DHF.

Study on the mechanism of ginsenoside Rg5 attenuating radiation myocarditis through GDF11-SIRT1 pathway.

e15098 Background: Radiation-induced Heart Disease (RIHD) refers to the damage caused by the radiation dose to the heart during radiotherapy for malignant tumors (especially chest tumors), generally including myocardial disease, pericardial disease, coronary artery disease, etc. It generally occurs during radiotherapy or within months to years after radiotherapy. It is reported that the incidence within 5-10 years after the end of radiotherapy is about 10%-30%. With the advancement of equipment and technology, radiotherapy has become increasingly involved in malignant tumors and has become one of the most important treatments for thoracic tumors. Radiation heart disease will significantly reduce the quality of life of patients with malignant tumors after radiotherapy. and survival rate. Although the incidence of RIHD can be reduced by optimizing radiotherapy technology, current technology cannot eliminate the risk of RIHD4. Therefore, it is of great clinical significance to explore how to reduce the incidence and severity of radiation heart disease. Methods: In vitro cultured cardiomyocyte model: used to analyze the impact of Rg5 on cardiomyocytes at the molecular level. Animal model: Construct an animal model of radiation heart disease to evaluate the protective effect of Rg5. Construction of iPCS organoid model to verify that Rg5 attenuates radiation heart disease mediated through Sirt1. Results: Immunohistochemistry, HE staining and Masson staining in early animal experiments showed that Rg5 can slow down radiation heart disease caused by radiotherapy. Immunohistochemistry results showed that SIRT1, HDAC3, PINK1, PARKIN, MFN2 and GDF11 showed obvious differences in expression, while SIRT6 and DRP1 did not. There were obvious differences. At the same time, immunofluorescence double staining of DRP1+SIRT1, MFN2+SIRT1, and HDAC3+SIRT1 was further performed to clarify their intracellular spatial relationship. After using iPSCs to induce cardiac endothelial cells, double immunofluorescence staining of mitochondrial markers and endothelial marker CD31 was performed. The results showed that radiotherapy can cause damage to vascular endothelial cells, reduce vascular integrity, reduce mitochondrial length, and impair function. Ginsenoside Rg5 can reduce this trend. From the common database of single-cell myocardial tissue, it was found that markers such as SIRT1, HDAC3, PINK1, MFN2, GDF11, and GPX4 have similar expression profiles in cardiomyocytes and are more likely to regulate each other. Conclusions: Ginsenoside Rg5 can regulate cardiac radiation injury through the HSP90α-HDAC3-GDF11-SIRT1 axis.It is expected to provide new therapeutic targets for the prevention and treatment of radiation heart disease, making ginsenoside Rg5 of great value in radiotherapy sensitization and radiation heart protection.

PD-1 Inhibitor Aggravate Irradiation-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads Signaling Pathway via GSDMD-Mediated Pyroptosis.

Cancer therapy has entered a new era with the use of programmed cell death protein 1 (PD-1) immune checkpoint inhibitors. When combined with thoracic radiotherapy, it demonstrates synergistic anti-tumor effects and potentially worsens radiation-induced myocardial fibrosis (RIMF). RIMF is the final stage of radiation-induced heart disease (RIHD) and a potentially fatal clinical complication of chest radiotherapy. It is characterized by decreased ventricular elasticity and distensibility, which can result in decreased ejection fraction, heart failure, and even sudden cardiac death. Pyroptosis, a type of programmed cell death, is mediated by members of the gasdermin (GSDM) family and has been associated with numerous cardiac disorders. The effect of pyroptosis on myocardial fibrosis caused by a combination of radiotherapy and PD-1 inhibitors remains uncertain. In this study, a 6MV X-ray of 20Gy for local heart irradiation was used in the RIHD mouse model. We noticed that PD-1 inhibitors aggravated radiation-induced cardiac dysfunction and RIMF, concurrently enhancing the presence of CD8+ T lymphocytes in the cardiac tissue. Additionally, our findings indicated that the combination of PD-1 inhibitor and thoracic radiation can stimulate caspase-1 to cleave GSDMD, thereby regulating pyroptosis and liberating interleukin-8 (IL-18). In the myocardium of mice, the manifestation of pyroptosis mediated by GSDMD is accompanied by the buildup of proteins associated with fibrosis, such as collagen I, transforming growth factor β1 (TGF-β1), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumornecrosisfactorα (TNF-α). Moreover, it was discovered that TFG-β1 induced the phosphorylation of Smad2/Smad3 when the cardiac underwent PD-1 inhibitor in conjunction with thoracic irradiation (IR). The findings of this research indicate that PD-1 inhibitor worsen RIMF in mice by triggering GSDMD-induced pyroptosis and influencing the TGF-β1/Smads pathway. While using the caspase-1 inhibitor Z-YVAD-FMK, RIMF can be alleviated. Blocking GSDMD may be a viable strategy for managing myocardial fibrosis caused by the combination of PD-1 inhibitors and radiotherapy.

The Proteoglycans Biglycan and Decorin Protect Cardiac Cells against Irradiation-Induced Cell Death by Inhibiting Apoptosis

Radiation-induced heart disease (RIHD), a common side effect of chest irradiation, is a primary cause of mortality among patients surviving thoracic cancer. Thus, the development of novel, clinically applicable cardioprotective agents which can alleviate the harmful effects of irradiation on the heart is of great importance in the field of experimental oncocardiology. Biglycan and decorin are structurally related small leucine-rich proteoglycans which have been reported to exert cardioprotective properties in certain cardiovascular pathologies. Therefore, in the present study we aimed to examine if biglycan or decorin can reduce radiation-induced damage of cardiomyocytes. A single dose of 10 Gray irradiation was applied to induce radiation-induced cell damage in H9c2 cardiomyoblasts, followed by treatment with either biglycan or decorin at various concentrations. Measurement of cell viability revealed that both proteoglycans improved the survival of cardiac cells post-irradiation. The cardiocytoprotective effect of both biglycan and decorin involved the alleviation of radiation-induced proapoptotic mechanisms by retaining the progression of apoptotic membrane blebbing and lowering the number of apoptotic cell nuclei and DNA double-strand breaks. Our findings provide evidence that these natural proteoglycans may exert protection against radiation-induced damage of cardiac cells.

Cardiac conduction system as anew organ at risk in radiotherapy.

Cardiovascular diseases represent the most common non-oncologic cause of death in patients following radiotherapy (RT) in the thoracic region. Radiation-induced heart disease (RIHD) can manifest as various heterogeneous clinical entities. However, the influence of RT on the cardiac conduction system has only recently gained more attention. Arrhythmogenic toxicity, i.e., conduction disorders and arrhythmias, constitutes asignificant part of these adverse effects. The cardiac conduction system is not routinely monitored as an organ at risk (OaR). Its specific histological nature and function suggest different sensitivity and response to radiation. The heart is ahighly heterogeneous organ, and the routinely monitored dose to the whole heart may not adequately characterize the risk of increased arrhythmogenic toxicity from RT. Cardiac structures, including the conduction system, appear to be additional OaRs for which dose distribution should be monitored. For the systematic selection of studies, we utilized the PubMed database with keywords derived from the analysis of existing literature. The search was limited to English-language publications, and the selection criteria included relevance to the topic and the quality of methodology. This article summarizes the impact of RT on the cardiac conduction system. Radiotherapy-induced cardiotoxicity significantly affects morbidity and mortality. The heart exhibits heterogeneity in terms of radiosensitivity. Certain cardiac subregions in the dose distribution show ahigher correlation with poorer overall survival than routinely monitored doses to the whole heart and derived parameters (the volumes irradiated with the doses of 5or 30Gy - V5or V30, respectively). The most radiosensitive subregions appear to be the base of the heart, including the beginning of the conduction system. Higher doses to the conduction system, especially the sinoatrial (SA) node, are associated with ahigher incidence of awide range of arrhythmias and poorer overall survival. However, dose limits (Dmean and Dmax) for the conduction system have not yet been established. Dosimetric studies have identified cutoff doses to the SA node, exceeding which there is asignificant increase in mortality and the occurrence of arrhythmias.

FLASH Proton Radiation Therapy Mitigates Inflammatory and Fibrotic Pathways and Preserves Cardiac Function in a Preclinical Mouse Model of Radiation-Induced Heart Disease

PurposeStudies during the past 9 years suggest that delivering radiation at dose rates exceeding 40 Gy/s, known as “FLASH” radiotherapy, enhances the therapeutic index of radiation therapy (RT) by decreasing normal tissue damage while maintaining tumor response compared to conventional (or standard) RT. This study demonstrates the cardioprotective benefits of FLASH proton RT (F-PRT) compared to standard (conventional) proton RT (S-PRT), as evidenced by reduced acute and chronic cardiac toxicities. Methods and MaterialsMice were imaged using cone beam computed tomography to precisely determine the heart's apex as the beam isocenter. Irradiation was conducted utilizing a shoot-through technique with a 5mm diameter circular collimator. Bulk RNA-sequencing was performed on non-irradiated (NR) samples, as well as apexes treated with F-PRT or S-PRT, at 2 weeks following a single 40 Gy dose. Inflammatory responses were assessed through multiplex cytokine/chemokine microbead assay and immunofluorescence analyses. Levels of perivascular fibrosis were quantified using Masson's Trichrome and Picrosirius red staining. Additionally, cardiac tissue functionality was evaluated by 2D echocardiograms at 8 and 30 weeks post-PRT. ResultsRadiation damage was specifically localized to the heart's apex. RNA profiling of cardiac tissues treated with PRT revealed that S-PRT uniquely upregulated pathways associated with DNA damage response, induction of tumor necrosis factor superfamily and inflammatory response, while F-PRT primarily affected cytoplasmic translation, mitochondrion organization and ATP synthesis. Notably, F-PRT led to a milder inflammatory response, accompanied by significantly attenuated changes in TGF-β1 and αSMA levels. Critically, F-PRT decreased collagen deposition, and better preserved cardiac functionality compared to S-PRT. ConclusionsThis study demonstrated that F-PRT reduces the induction of an inflammatory environment with lower expression of inflammatory cytokines and profibrotic factors. Importantly, the results indicate that F-PRT better preserves cardiac functionality, as confirmed by echocardiography analysis, while also mitigating the development of long-term fibrosis.

Advances in injectable hydrogels for radiation-induced heart disease

Radiological heart damage (RIHD) is damage caused by unavoidable irradiation of the heart during chest radiotherapy, with a long latency period and a progressively increasing proportion of delayed cardiac damage due to conventional doses of chest radiotherapy. There is a risk of inducing diseases such as acute/chronic pericarditis, myocarditis, delayed myocardial fibrosis and damage to the cardiac conduction system in humans, which can lead to myocardial infarction or even death in severe cases. This paper details the pathogenesis of RIHD and gives potential targets for treatment at the molecular and cellular level, avoiding the drawbacks of high invasiveness and immune rejection due to drug therapy, medical device implantation and heart transplantation. Injectable hydrogel therapy has emerged as a minimally invasive tissue engineering therapy to provide necessary mechanical support to the infarcted myocardium and to act as a carrier for various bioactive factors and cells to improve the cellular microenvironment in the infarcted area and induce myocardial tissue regeneration. Therefore, this paper combines bioactive factors and cellular therapeutic mechanisms with injectable hydrogels, presents recent advances in the treatment of cardiac injury after RIHD with different injectable gels, and summarizes the therapeutic potential of various types of injectable hydrogels as a potential solution.

Protective effect of naringin against radiation-induced heart disease in rats via Sirt1/NF-κB signaling pathway and endoplasmic reticulum stress.

This study was designed to explore the protective effect and mechanism of naringin (NG) on radiation-induced heart disease (RIHD) in rats. Rats were divided into four x-ray (XR) irradiation groups with different absorbed doses (0/10/15/20 Gy), or into three groups (control, XR, and XR + NG groups). Subsequently, the ultrasonic diagnostic apparatus was adopted to assess and compare the left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular internal diameter at end diastole (LVIDd), and left ventricular internal diameter at end systole (LVIDs) in rats. Hematoxylin-eosin (H&E) staining and Masson staining were applied to detect the pathological damage and fibrosis of heart tissue. Western blot was used to measure the expression levels of myocardial fibrosis-related proteins, endoplasmic reticulum stress-related proteins, and Sirt1 (silent information regulator 1)/NF-κB (nuclear factor kappa-B) signaling pathway-related proteins in cardiac tissues. Additionally, enzyme-linked immunosorbent assay was utilized to detect the activities of pro-inflammatory cytokines, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) in cardiac tissue. The results showed that NG treatment significantly attenuated the 20 Gy XR-induced decline of LVEF and LVFS and the elevation of LVIDs. Cardiac tissue damage and fibrosis caused by 20 Gy XR were significant improved after NG treatment. Meanwhile, in rats irradiated by XR, marked downregulation was identified in the expressions of fibrosis-related proteins (Col I, collagen type I; α-SMA, α-smooth muscle actin; and TGF-β1, transforming growth factor-beta 1) and endoplasmic reticulum stress-related proteins (GRP78, glucose regulatory protein 78; CHOP, C/EBP homologous protein; ATF6, activating transcription factor 6; and caspase 12) after NG treatment. Moreover, NG treatment also inhibited the production of pro-inflammatory cytokines [interleukin-6, interleukin-1β, and monocyte chemoattractant protein-1 (MCP-1)], reduced the expression of MDA, and promoted the activities of SOD and CAT. Also, NG treatment promoted Sirt1 expression and inhibited p65 phosphorylation. Collectively, XR irradiation induced cardiac injury in rats in a dose-dependent manner. NG could improve the cardiac injury induced by XR irradiation by inhibiting endoplasmic reticulum stress and activating Sirt1/NF-κB signaling pathway.

When radiation meets the heart: Future of stereotactic body radiation therapy for hypertrophic obstructive cardiomyopathy.

Hypertrophic obstructive cardiomyopathy (HOCM) is a hereditary cardiac disorder characterized primarily by septal hypertrophy and left ventricular outflow tract obstruction. Traditional therapeutic modalities, such as medications and surgeries, do not yield satisfactory outcomes in a subset of patients. The advancements have been made in novel treatments, including new drugs and percutaneous intramyocardial septal radiofrequency ablation (PIMSRA), still need further observation to obtain long-term efficacy and safety. In recent years, stereotactic body radiation therapy (SBRT) has emerged as an innovative non-invasive approach for treating HOCM. Studies indicate that SBRT allows for precise targeting of the hypertrophied septal region, causing both direct and indirect damage to targeted myocardial cells. This can alleviate left ventricular outflow tract obstruction and myocardial ischemia, fulfilling the therapeutic objective. For those with HOCM who neither respond well to medications nor are surgical candidates, SBRT offers a potential new therapeutic alternative. However, the latent risks of radiation therapy persist, such as the onset of radiation-induced heart disease (RIHD). The preliminary investigations guarantee the safety and feasibility of SBRT in HOCM management, an increased volume of clinical studies and prolonged follow-up data are essential to evaluate its real efficacy and potential hazards. In addition, research regarding the therapeutic mechanisms of SBRT for HOCM, optimal dosages and treatment durations, indications and contraindications, prevention of complications, and enhancing the precision of radiation therapy, still needs to be further exploration, to determine the best therapeutic strategies.

Deep learning–based automatic segmentation of cardiac substructures for lung cancers

PurposeAccurate and comprehensive segmentation of cardiac substructures is crucial for minimizing the risk of radiation-induced heart disease in lung cancer radiotherapy. We sought to develop and validate deep learning–based auto-segmentation models for cardiac substructures. Materials and MethodsNineteen cardiac substructures (whole heart, 4 heart chambers, 6 great vessels, 4 valves, and 4 coronary arteries) in 100 patients treated for non-small cell lung cancer were manually delineated by two radiation oncologists. The valves and coronary arteries were delineated as planning risk volumes. An nnU-Net auto-segmentation model was trained, validated, and tested on this dataset with a split ratio of 75:5:20. The auto-segmented contours were evaluated by comparing them with manually drawn contours in terms of Dice similarity coefficient (DSC) and dose metrics extracted from clinical plans. An independent dataset of 42 patients was used for subjective evaluation of the auto-segmentation model by 4 physicians. ResultsThe average DSCs were 0.95 (+/– 0.01) for the whole heart, 0.91 (+/– 0.02) for 4 chambers, 0.86 (+/– 0.09) for 6 great vessels, 0.81 (+/– 0.09) for 4 valves, and 0.60 (+/– 0.14) for 4 coronary arteries. The average absolute errors in mean/max doses to all substructures were 1.04 (+/– 1.99) Gy and 2.20 (+/– 4.37) Gy. The subjective evaluation revealed that 94% of the auto-segmented contours were clinically acceptable. ConclusionWe demonstrated the effectiveness of our nnU-Net model for delineating cardiac substructures, including coronary arteries. Our results indicate that this model has promise for studies regarding radiation dose to cardiac substructures.