Radiation-induced Heart Disease Research Articles

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.

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.

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.

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.

Is dobutamine stress echocardiography a good screening tool for coronary artery disease in breast cancer patients that underwent treatment with radiotherapy?

Abstract INTRODUCTION Accelerated atherosclerosis has been described in breast cancer patients receiving cardiac exposure from adjuvant radiotherapy (RT). As a result of multidisciplinary care, breast cancer cure rates have improved in recent decades. Therefore, evaluating radiation-induced heart disease (RIHD), especially coronary artery disease (CAD), is essential. The 2022 cardio-oncology European Society of Cardiology (ESC) guidelines recommend screening patients 5 to 10 years after RT for CAD according to cardiovascular risk factors. This screening is generally recommended with exercise stress echocardiography since it can assess the physiological functional performance. Until now, it is unknown if dobutamine stress echocardiography (DSE) is an equal screening tool and if it can predict major adverse cardiovascular events (MACE) (myocardial infarction, stroke, cardiac death, revascularization). PURPOSE Evaluate if DSE is an adequate tool to stratify and predict MACE in post-radiotherapy patients. Methods A retrospective, descriptive cohort study was conducted. Patients who had chest RT for breast cancer and underwent DSE from 2000 to 2022 were included. A bivariate analysis, including Kruskal Wallis and Pearson Chi-Squared test, was done to identify variables associated with a positive DSE. A multivariable Cox Model for MACE and a time-to-event curve for MACE were also performed. Results We identified 163 patients that underwent DSE after a median time of 5.8 years from the end of RT. The median age was 74 years, 98.2% were female, 50% had left and 45% right breast cancer, 81% had hypertension, 41% diabetes mellitus, 71% dyslipidemia, 34% were smokers, and 19% had a prior myocardial infarction. The average dose of photon RT to the chest was 55Gy in the cohort, and 40% received chemotherapy before RT. Patients were divided into two groups: positive and negative DSE. A positive DSE was seen in 19.6%. The median (Q1, Q3) regional wall motion abnormalities (RWMA) of patients with a positive DSE was 1 (1, 1.015) at baseline and 1.280 (1.190, 1.520) at peak stress, and for a negative DSE, was 1 (1, 1) at baseline and peak stress. 88.2% of negative DSE and 87.5% of positive DSE achieved the target heart rate of 85%. HTN, dyslipidemia, and prior MI were significantly associated with a positive DSE (p <0.023). The cumulative incidence of MACE was higher in the group of positive DSE (p<0.001), even after adjusting for hypertension, diabetes mellitus, dyslipidemia, smoking, and prior myocardial infarction, with a hazard ratio of 2.500 (1.51 – 4.13) and a p< 0.001. Similar results were observed regardless of RT laterality. Conclusions In breast cancer survivors that received adjuvant radiotherapy as part of multidisciplinary care, a positive DSE was an independent predictor of MACE compared to a negative result. These results support the usefulness of dobutamine stress echocardiography as a screening tool in breast cancer survivors.Kaplan-Meier Curve for MACE

Contemporary review: recognition, management, and screening for radiation-induced heart disease

Radiation is a primary therapy in the treatment of thoracic malignancies with clear survival benefits. Consequently, patients with cancer are living longer but may be subject to a wide array of cardiotoxic effects from collateral radiation damage. Ensuing fibrosis can affect any portion of the cardiac parenchyma, increasing the risk for accelerated coronary artery disease, pericardial sequelae such as constrictive pericarditis, valvulopathy, restrictive cardiomyopathy, and a myriad of conduction system abnormalities. Unfortunately, the effects of cardiotoxicity can be subclinical or delayed and there remains an unmet need to standardize management strategies for these patients. Based on current data, it is prudent to consider percutaneous approaches first for coronary and valvular disease and traditional, supportive measures for the remaining sequelae. Every attempt should be made to undergo a complete operative haul due to the increased risks of re-operation if surgery is to be performed. Surrounding the patient with a multidisciplinary heart team is critical.

Single-Cell RNA Sequencing Reveals a Subset of cMAS can Aggravate RIHD through CXCL1-CXCR2 Axis

Radiation induced heart disease (RIHD) is any form of cardiac toxicity induced by radiation therapy (RT) for thoracic cancers. Our previous studies have shown that RT obviously contributed to cardiovascular diseases-specific death over 3 years while RT became protective in the short term within 2 years survival in non-small cell lung cancer patients. Here, single cell RNA sequencing (scRNA-seq) was performed to identify various cell subsets and investigate their functions and dynamics in RIHD which offered several targets for early clinical interventions to alleviate RIHD. Based on evaluation of histopathological characteristics, ejection fraction and serum levels of cardiac injury biomarkers, we have established mouse models during different stages to simulate clinical RIHD progression. Hence, we performed single cell RNA-sequencing of RIHD models to characterize the diversity within specific cell types and obtain basic information of differently expressed genes (DEGs). We investigated the role of several cell clusters and DEGs in RIHD through bioinformatics analysis and experimental verification. In vivo, mouse models were given intraperitoneal injection of CXCR2 inhibitor. Bone marrow macrophages and primary cardiac fibroblasts were extracted for in vitro experiments. RIHD processes were divided into acute injury, compensation and decompensation stage. Transcriptomes of 31769 single cells from cardiac suspension have been profiled. Analysis of scRNA-seq revealed that there were 30 cell clusters participating in RIHD. The fraction of cell populations varied greatly at three stages which indicated RIHD was a dynamic process and each cell cluster functioned differently at different stages. Notably, we observed cardiac resident macrophages (cMAS) subset accounted for the highest fraction during the compensatory period and decreased in decompensation period. Pseudotime analysis showed cMAS had a different developmental trajectory compared to myeloid derived cells. Moreover, CXCR2 was significantly expressed in cMAS cluster. Ligand-receptor interaction results suggested that CXCL1 secreted by cardiac fibroblasts bind primarily to CXCR2+ cMAS and participated in the formation of the extracellular matrix (ECM) related to cardiac fibrosis. Moreover, cardiac fibrosis of RIHD models were relieved after CXCR2 inhibitor treatment. CXCL1 expression in primary cardiac fibroblast elevated after RT. The identification of main cell clusters provided a new insight to investigate RIHD through dynamics of cell phenotypes and cell-cell communications during RIHD processes. In compensation stage, CXCR2+ cMAS could be activated by CXCL1 secreted by cardiac fibroblasts. Both were associated with ECM and contribute to the decompensation stage.

The Early and Late Effects of High-Dose Irradiation on Cardiac Injury in a Rat Model

Radiation-induced heart disease is a critical concern after radiotherapy (RT) for thoracic and chest wall tumors; however, the biological effects and mechanisms are still unknown. In this study, we investigated dose-responsive functional and pathological changes in rat hearts at 1, 3, and 5 months after high-dose irradiation. Then, we sought to elucidate the underlying mechanisms of myocardial changes induced by high-dose irradiation. Whole hearts of rats (N = 72) were irradiated with a single fraction of 0 (control), 10, 20, or 30 Gy and allocated into three groups according to the follow-up period after RT: baseline, one, three, and five months. During follow-up periods, rats underwent functional evaluation by electrocardiogram and echocardiography at 4-week intervals. If a rat's body weight decreased by 20% or more, it was considered premature death, and the heart was explanted immediately. Otherwise, all hearts were explanted when each group's follow-up period was completed. Pathological changes of cardiac structures were evaluated using a light microscope after staining with hematoxylin-eosin, Masson's trichrome, α-smooth muscle actin, desmin, and connexin-43. All rats irradiated with 0 or 10 Gy completed their follow-up periods with continuously increasing body weight. However, among rats irradiated with 20 or 30 Gy, half of the rats died prematurely at 8-10 weeks after RT, and the remainder survived until 20 weeks. In echocardiography, increased wall thickness and E/E' ratio, and decreased end-diastolic volume were observed in 20-30 Gy groups compared to 0-10 Gy groups from 8 weeks after RT. Ejection fraction was preserved in all groups. In pathological review, 20-30 Gy groups demonstrated diffuse inflammation and vacuolization at 4 weeks. Then, at 8 weeks, prominent fibrotic changes and intercalated disc disruptions were observed. Notably, fibrotic changes were somewhat resolved at 20 weeks, but intercalated disc disruptions were not repaired until 20 weeks. The 0 and 10 Gy groups showed no significant changes in both functional and pathological analyses. Rats irradiated with 20 or 30 Gy showed diastolic dysfunction in functional analysis and time-dependent myocardial changes in pathological analysis. Radiation-induced fibrosis might be a "reactive" fibrosis, which could proceed to either a profibrotic course (progressive fibrosis) or an anti-fibrotic course (recovery phase). Further studies are needed to identify whether high-dose irradiation-induced cardiac fibrosis could be reversible.

Fullerenols Mitigate Radiation-Induced Myocardial Injury.

Radiation-induced heart disease is a serious side effect of radiation therapy that can lead to severe consequences. However, effectiveandsafe methods for their prevention and treatment are presently lacking. This study reports the crucial functionoffullerenolsin protecting cardiomyocytes fromradiation injury. First, fullerenols are synthesized using a simple base-catalyzed method. Next, the as-prepared fullerenols are applied as an effective free radical scavenger andbroad-spectrumantioxidant to protect against X-ray-induced cardiomyocyte injury. Their ability to reduce apoptosis via the mitochondrial signaling pathway at the cellular level is then verified. Finally, it is observed in animal models that fullerenols accumulate in the heart and alleviate myocardial damage induced by X-rays. This study represents a timely and essential analysis of the prevention and treatment of radiological myocardial injury, providing new insights into the applications of fullerenols for therapeutic strategies.

Uncommon short- and long-term cardiological side effects of thoracic radiation: a report of two cases.

Radiotherapy is an essential treatment of more than 50% of oncohematological patients. Pericardial disorders and valvular heart disease are two common radiotherapy complications. Acute pericarditis is infrequent and usually underdiagnosed. Therefore, diagnostic suspicion and early treatment are mandatory to avoid the evolution to constrictive pericarditis. The prevalence of radiation-induced valvular heart disease is common in patients with a history of Hodgkin's lymphoma and breast cancer. It has distinctive characteristics from other etiologies and, thus, different therapeutic approaches. We present two cases of unusual complications of radiotherapy; the first one in the acute setting and the second one during the follow-up in the chronic phase. A multidisciplinary and individualized approach with specific considerations is decisive in the management of these patients.

A pooled analysis of nine studies in one institution to assess effects of whole heart irradiation in rat models

Purpose Over the years, animal models of local heart irradiation have provided insight into mechanisms of and treatments for radiation-induced heart disease in human populations. However, it is not completely clear which manifestations of radiation injury are most commonly seen after whole heart irradiation, and whether certain biological factors impact experimental results. Combining 9 homogeneous studies in rat models of whole heart irradiation from one laboratory, we sought to identify experimental and/or biological factors that impact heart outcomes. We evaluated the usefulness of including (1) heart rate and (2) bodyweight as covariates when analyzing biological parameters, and (3) we determined which echocardiography, histological, and immunohistochemistry parameters are most susceptible to radiation effects. Finally, (4) as an educational example, we illustrate a hypothetical sample size calculation for a study design commonly used in evaluating radiation modifiers, using the pooled estimates from the 9 rat studies only for context. The results may assist investigators in the design and analyses of pre-clinical studies of whole heart irradiation. Materials and Methods We made use of data from 9 rat studies from our labs, 8 published elsewhere in 2008–2017, and one unpublished study. Echocardiography, histological, and immunohistochemical parameters were collected from these studies. Using mixed effects analysis of covariance models, we estimated slopes for heart rate and bodyweight and estimated the radiation effect on each of the parameters. Results Bodyweight was related to most echocardiography parameters, and heart rate had an effect on echocardiography parameters related to the diameter of the left ventricle. For some parameters, there was evidence that heart rate and bodyweight relationships with the parameter depended on whether the rats were irradiated. Radiation effects were found in systolic measures of echocardiography parameters related to the diameter of the left ventricle, with ejection fraction and fractional shortening, with atrial wall thickness, and with histological measures of capillary density, collagen deposition, and mast cells infiltration in the heart. Conclusion Accounting for bodyweight, as well as heart rate, in analyses of echocardiography parameters should reduce variability in estimated radiation effects. Several echocardiography and histological parameters were particularly susceptible to whole heart irradiation, showing robust effects compared to sham-irradiation. Lastly, we provide an example approach for a sample size calculation that will contribute to a rigorous study design and reproducibility in experiments studying radiation modifiers.

CardioMEMS in Radiation-Induced Heart Disease: Outcomes From a Single0Center Case Series

CardioMEMS in Radiation-Induced Heart Disease: Outcomes From a Single0Center Case Series

Radiopaque and X-ray-Responsive Nanomedicine for Preventive Therapy of Radiation-Induced Heart Disease.

Radiation-induced heart disease (RIHD) is a common radiotherapy complication. Reducing radiation exposure and post-irradiation antioxidant therapy are promising approaches. Here, a liquid metal-based core-shell nanomedicine (LMN) composed of a gallium core and a multifunctional polymeric shell with radiopaque, X-ray shielding, and X-ray-responsive antioxidation properties for preventive therapy of RIHD is developed. The liquid metal provides radiopaque properties to enhance X-ray and computed tomography imaging and attenuate radiation to prevent primary myocardial damage. Under X-ray radiation, cleavage of the diselenide bond on the polymeric shell results in the release of LMN and controlled antioxidation. In vitro and in vivo experiments have demonstrated that LMN significantly reduces myocardial injury and impaired cardiac function, stabilizes mitochondrial function, and inhibits myocardial fibrosis. This nanomedicine with radiographic contrast, radiation shielding, and responsive features provides a new strategy for the prevention of radiation-related diseases.

MAGNETIC RESONANCE IMAGING EVALUATION OF INCIDENTAL CARDIAC IRRADIATION DURING LEFT BREAST CANCER RADIOTHERAPY: A SYSTEMATIC REVIEW

Breast cancer is one of the most common malignant tumours among women. Radiotherapy plays a key role in the management of breast cancer patients. However, radiotherapy results in incidental exposure of the heart. This work systematically reviewed articles on magnetic resonance imaging (MRI) evaluation of cardiac changes due to incidental cardiac irradiation during left breast radiotherapy and also to identify the MRI sequences used during evaluation. A systematic literature search was conducted in the following three selected databases: PubMed, ScienceDirect and Scopus using carefully defined search terms related to the left breast, MRI and cardiac irradiation. The quality of the included papers was determined using the critical appraisal skills programme for qualitative studies. The review had a total of six articles that were screened and graded for quality. Articles graded as high and moderate in terms of quality assessment were included and characterised based on the sample size, type of cancer treated, treatment methods employed, and period MRI was performed after radiotherapy. The review showed that breast cancer patients who had radiotherapy also developed radiation-induced heart disease (RIHD) few months post treatment. The review noted that breast cancer patients receiving radiation treatment are at high risk of RIHD which may affect their quality of life after completion of treatment. Cardiac MRI facilitates early detection of RIHD, hence better patient management.

РАДИАЦИОННО-ИНДУЦИРОВАННАЯ БОЛЕЗНЬ СЕРДЦА: ПРИЧИНЫ, ПРОЯВЛЕНИЯ, ПРОФИЛАКТИКА

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

PTPMT1 protect cardiomyocytes from necroptosis induced by γ-ray irradiation through alleviate mitochondria injury.

Radiation-induced heart disease (RIHD) progresses over time and may manifest decades after the initial radiation exposure, which is associated with significant morbidity and mortality. The clinical benefit of radiotherapy is always counterbalanced by an increased risk of cardiovascular events in survivors. There is an urgent need to explore the effect and the underlying mechanism of radiation-induced heart injury. Mitochondrial damage widely occurs in irradiation-induced injury, and mitochondrial dysfunction contributes to necroptosis development. Experiments were performed using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and rat H9C2 cells to investigate the effect of mitochondrial injury on necroptosis in irradiated cardiomyocytes and to further elucidate the mechanism underlying radiation-induced heart disease and discover possible preventive targets. After γ-ray irradiation, the expression levels of necroptosis markers were increased, along with higher oxidative stress and mitochondrial injury. These effects could be abated by overexpression of PTEN-like mitochondrial phosphatase (PTPMT1). Inhibiting oxidative stress or increasing the expression of PTPMT1 could protect against radiation-induced mitochondrial injury and then decrease the necroptosis of cardiomyocytes. These results suggest that PTPMT1 may be a new target for the treatment of radiation-induced heart disease.

Analysis of heart displacement during thoracic radiotherapy based on electrocardiograph-gated 4-dimensional magnetic resonance imaging.

Periodic cardiac movement may expose the heart to radiation field induced damage, leading to radiation-induced heart disease (RIHD). Studies have proven that delineation of the heart based on planning CT fails to show the real margin of the substructures and a compensatory margin should be applied. The purpose of this study was to quantify the dynamic changes and the compensatory extension range by breath-hold and electrocardiogram gated 4-dimensional magnetic resonance imaging (4D-MRI), which had the advantage of discriminating soft tissues. Eventually, 15 patients with oesophageal or lung cancers were enrolled, including one female and nine males aged from 59 to 77 years from December 10th, 2018, to March 4th, 2020. The displacement of the heart and its substructures was measured through a fusion volume and the compensatory expansion range was calculated by expending the boundary on the planning CT to that of the fusion volume. The differences were tested through the Kruskal-Wallis H test and were considered significant at a two-side P<0.05. The extent of movement of heart and its substructures during one cardiac cycle were approximately 4.0-26.1 millimetre (mm) in anterior-posterior (AP), left-right (LR), and cranial-caudal (CC) axes, and the compensatory margins should be applied to planning CT by extending the margins by 1.7, 3.6, 1.8, 3.0, 2.1, and 2.9 centimetres (cm) for pericardium; 1.2, 2.5, 1.0, 2.8, 1.8, and 3.3 cm for heart; 3.8, 3.4, 3.1, 2.8, 0.9, and 2.0 cm for interatrial septum; 3.3, 4.9, 2.0, 4.1, 1.1, and 2.9 cm for interventricular septum; 2.2, 3.0, 1.1, 5.3, 1.8, and 2.4 cm for left ventricular muscle (LVM); 5.9, 3.4, 2.1, 6.1, 5.4, and 3.6 cm for antero-lateral papillary muscle (ALPM); and 6.6, 2.9, 2.6, 6.6, 3.9, and 4.8 cm for postero-medial papillary muscle (PMPM) in anterior, posterior, left, right, cranial, and caudal directions, respectively. Periodic cardiac activity causes obvious displacement of the heart and its substructures, and the motion amplitude of substructures differs. Extending a certain margin as the compensatory extension to represent the organs at risk (OAR) and then limiting the dose-volume parameters could be performed in clinical practice.

TLR4-A Pertinent Player in Radiation-Induced Heart Disease?

The heart is one of the organs that is sensitive to developing delayed adverse effects of ionizing radiation (IR) exposure. Radiation-induced heart disease (RIHD) occurs in cancer patients and cancer survivors, as a side effect of radiation therapy of the chest, with manifestation several years post-radiotherapy. Moreover, the continued threat of nuclear bombs or terrorist attacks puts deployed military service members at risk of exposure to total or partial body irradiation. Individuals who survive acute injury from IR will experience delayed adverse effects that include fibrosis and chronic dysfunction of organ systems such as the heart within months to years after radiation exposure. Toll-like receptor 4 (TLR4) is an innate immune receptor that is implicated in several cardiovascular diseases. Studies in preclinical models have established the role of TLR4 as a driver of inflammation and associated cardiac fibrosis and dysfunction using transgenic models. This review explores the relevance of the TLR4 signaling pathway in radiation-induced inflammation and oxidative stress in acute as well as late effects on the heart tissue and the potential for the development of TLR4 inhibitors as a therapeutic target to treat or alleviate RIHD.