Advances in radiation-induced heart disease diagnosis and treatment
Published Online: 30 April 2024
Abstract
Over the past decades, the survival rates of patients with cancer have significantly increased owing to advancements in cancer treatment strategies. Radiotherapy has become an indispensable treatment modality for thoracic tumors. While it offers benefits in treating or even potentially curing cancer, thoracic radiotherapy exposes neighboring heart tissues to ionizing radiation, elevating the risk of radiation-induced heart disease (RIHD). Despite improvements in radiotherapy techniques that have reduced the incidence of RIHD, complete avoidance of heart radiation exposure remains a challenge. Cohort studies involving atomic bomb survivors and individuals with occupational radiation exposure, even at relatively low doses, have reported a significant increase in RIHD risks. The pathological mechanisms underlying RIHD have been extensively reviewed. At present, imaging techniques and traditional cardiac biomarkers are the primary methods to diagnose RIHD, with ongoing efforts to explore additional promising markers for predicting and monitoring RIHD. Moreover, traditional and novel therapeutic strategies are being actively explored to prevent or alleviate RIHD. Insights gained from therapeutic advancements in other organ systems or heart diseases caused by different factors can provide valuable ideas for RIHD management. This review discusses the recent advancements in the diagnosis and treatment of RIHD.
1. Introduction
Cancer mortality has gradually decreased over recent decades owing to early detection, advanced surgical approaches, improved radiotherapy (RT) and chemoradiotherapy. However, the advancement in anticancer efficacy has come with potential adverse effects on healthy organs, particularly the heart. Thoracic radiotherapy can harm various components of the heart, leading to radiation-induced heart disease (RIHD). RIHD can manifest as acute or chronic conditions, including coronary artery atherosclerosis, valvular disease, constrictive pericarditis, restrictive cardiomyopathy, arrhythmias, carotid artery disease, and other vascular diseases.1 The pathological changes associated with RIHD depend on several factors, such as the irradiated heart location, RT dose and technology, as well as age, hypertension history, and heart disease background. A meta-analysis indicated that women with left-sided breast cancer receiving RT faced a higher risk of cardiac mortality than those with right-sided breast cancer.2 Among patients with Hodgkin’s lymphoma receiving RT, the risk of coronary heart disease was found to increase by 7.4 % per Gy and was 2.5-fold higher than patients not receiving RT when the mean heart dose reached 20 Gy.3
In recent times, the emergence of approaches such as three-dimensional (3D) conformal RT, intensity-modulated RT, and proton beam therapy have progressively reduced cardiac radiation doses.4 In a cohort of 38 patients with early-stage Hodgkin’s lymphoma, optimized volumetric modulated arc therapy (VMRT) was reported to lower the risk of RIHD compared to 3D conformal RT.5 However, epidemiological studies have shown increased risks of RIHD in atomic bomb survivors or nuclear power industry workers exposed to low-dose radiation, suggesting the absence of a safety dose threshold for RIHD.6,7 Newer RT technologies using protons or high-charged energy ions are also associated with some cardiotoxic effects. A preclinical study on C57BL/6NT mice found that exposure to ionizing radiation composed of a spectrum of low-fluence protons and high-charge and energy iron nuclei induced cardiac fibrosis at 1 month and cardiac hypertrophy signaling at 3 months.8
Apart from RT-related factors, patient conditions also influence the presentation of RIHD. A multicenter study involving 2,524 patients with Hodgkin’s lymphoma demonstrated that younger patients were more susceptible to developing RIHD.9 Women with breast cancer and a history of ischemic heart disease and hypertension evidently show a higher risk of major coronary events post-RT than those without previous cardiovascular risk factors or history.10 Oncologists are therefore striving to treat patients with cancer using optimal therapeutic strategies without preserving cardiovascular health. Studies focusing on risk structure identification and defining threshold doses to heart volume are being conducted to strike a balance between effective anticancer treatment and adequate heart protection.11
To date, significant progress has been made in understanding the cellular and molecular mechanisms of RIHD.1 RT induces oxidative injuries in macromolecules (e.g., DNA, proteins, and lipids), leading to DNA damage, telomere erosion, mitochondrial dysfunction, epigenetic regulation, post-translational protein modifications, and metabolic alterations in various heart cell types. These mechanisms have been highlighted in multiple reviews.12,13,14 Herein we emphasize the diagnostic value of imaging techniques and traditional and novel biomarkers in diagnosing or predicting RIHD. We also discuss evidence-based therapeutic strategies to prevent or alleviate RIHD. Due to limited data on RIHD. We also discuss advancements in therapeutics for other radiation-induced non-cardiac or heart diseases (e.g., ischemia/reperfusion and chemotherapy-induced heart diseases) to support diagnostic and treatment strategies for RIHD in this review.
2. Diagnosis
Standard diagnostic strategies for RIHD typically involve imaging techniques and serum blood biomarker examinations. Magnetic resonance imaging (MRI) is considered more accurate than echocardiography and computed tomography (CT) in identifying RIHD, but its clinical application is limited due to high costs and poor availability. Troponins are the most commonly used biomarkers and are often used for RIHD screening. Elevated troponin levels prompt further imaging examinations to assess RIHD. Despite the emergence of novel biomarkers, their effectiveness in diagnosing and predicting RIHD has not been clinically validated yet.
2.1. Imaging techniques
2.1.1. Echocardiography
Echocardiography is widely employed for monitoring cardiac abnormalities related to cancer treatment owing to its advantages, including low cost, wide availability, rapid detection, and lack of radiation exposure.15 It can assess the left ventricular (LV) structure and evaluate cardiac systolic and diastolic function.16 Parameters such as LV ejection fraction (LVEF) and myocardial strain are commonly used in echocardiography to predict cancer treatment-related cardiotoxicity.17,18,19 Walker et al.20 monitored LVEF in patients with breast cancer and compared the role of 2D and 3D echocardiography, with cardiac MR imaging serving as the reference standard. They found that 3D echocardiography demonstrated a stronger correlation with cardiac MR imaging for LVEF assessment than 2D echocardiography. However, LVEF may not be sensitive enough to monitor cardiotoxicity in the early stages of RT; a significant decrease in LVEF is observed only when myocardial damage is substantial and compensatory mechanisms are overwhelmed. Notably, women with breast cancer have been observed to show no acute changes in LVEF when the heart dose was below 4 Gy.21
Strain rate imaging, a new echocardiography modality, was reported to show a subclinical decline in cardiac function as indicated by reduced LV strain in patients with breast cancer 14 months post-RT.22 This imaging technique may provide valuable predictions of RT-induced clinical outcomes by detecting abnormal myocardial strain. Global longitudinal strain (GLS) measured using speckle tracking echocardiography is a robust and sensitive parameter that accurately assesses global and regional cardiac systolic function.23 GLS-guided cardioprotective therapy has been successful in mitigating LVEF reduction among 307 patients treated with anthracycline.18 In addition, longitudinal systolic strain was found to decrease in patients with Hodgkin’s lymphoma receiving RT, with a more pronounced decline observed in those also receiving chemotherapy.24
Esmaeilzadeh et al.19 evaluated cancer therapy-related cardiac dysfunctions (anthracycline and trastuzumab) among 136 women with breast cancer using echocardiographic LVEF and strain and serum biomarkers, with cardiovascular MRI as the reference standard. They observed that the combined use of echocardiographic 3D LVEF, 2D GLS, and 2D global circumferential strain could optimize the diagnosis of MRI-defined cardiac dysfunction, whereas 2D LVEF, high-sensitivity troponin I (hsTnI), and B-type natriuretic peptide did not. In a nutshell, their findings suggested that a sequential approach combining 3D LVEF, 2D GLS, and 2D global circumferential strain provides a more timely and accurate diagnosis of cancer treatment-induced cardiac injury than using these parameters individually. The data also provided insights and indications for RIHD diagnosis.
2.1.2. MRI
MRI is considered the gold standard for evaluating cardiac structure and function, capable of detecting myocardial fibrosis, microcirculation abnormalities, pericardial lesions, myocardial ischemia, and myocardial infarction at an early stage. However, its high cost and poor availability restrict its routine use. In a prospective clinical trial involving 51 patients with left-sided breast cancer, MRI was utilized to predict RT-induced cardiotoxicity and subsequent cardiac events.25 Similarly, another study employed MRI to monitor RT-induced cardiotoxicity in 53 Hodgkin’s disease survivors, 70 % of whom exhibited cardiac pathological changes long after RT.26 Late gadolinium enhancement (LGE) is a cardiac MRI imaging technique to assess myocardial scar formation and fibrosis. Beukema et al.27 utilized LGE to identify cardiac fibrosis in esophageal cancer survivors undergoing neoadjuvant chemoradiation. MRI T1 mapping enables quantitative measurement of T1 value and extracellular volume in the myocardium to assess myocardial abnormalities, such as fibrosis and edema.28 MRI T2 mapping also reflects myocardial lesions, such as edema and inflammation, through T2 value measurement. Takagi et al.28 evaluated LV function and tissue composition using MRI imaging after chemotherapy-radiation therapy in participants with esophageal cancer and found that T1 mapping could identify myocardial changes earlier than LV stroke volume index or LGE. However, the potential value of LGE and T1 and T2 mapping in RIHD screening remains to be determined.
2.1.3. CT
CT is a promising imaging modality with various types. Single-photon emission CT has been applied to examine cardiac diseases. Zhang et al.29 identified the occurrence of cardiac impairment during RT in patients with locally advanced esophageal cancer using various parameters, such as wall motion, wall thickening, and heart rate. Another CT modality, angiography, plays a vital role in diagnosing coronary artery diseases and shows excellent sensitivity.30 Patients with Hodgkin’s lymphoma were found to be at a 15 % risk of CT angiography abnormalities within the first five years post-RT, and up to 34 % after 10 years31; furthermore, angiography results revealed severe stenoses in 6.7 % patients.31 Positron emission tomography (PET) is a noninvasive imaging test that can reveal metabolic or biochemical functions of tissues and organs. Fibroblast activation protein (FAP) is a promising target for diagnosing tissue remodeling following myocardial infarction, ischemia, and radiation-induced myocardial damage. Wei et al.32 employed radiolabeled FAP inhibitor (FAPI) to investigate the feasibility of 18FAlF-NOTA-FAPI-04 PET/CT for detecting radiation-induced myocardial damage in 13 patients with esophageal squamous cell cancer treated with concurrent chemoradiotherapy and observed increased FAPI uptake in the myocardium. Their findings verified that 18FAlF-NOTA-FAPI-04 PET/CT could noninvasively detect radiation-induced myocardial damage earlier than a decrease in LVEF. Above all, these data offer us insights into the role of CT in diagnosing RT-induced coronary diseases.
2.2. Biomarkers
2.2.1. Traditional biomarkers
Blood biomarkers serve as conventional tools for monitoring radiation-induced cardiotoxicity. Sample availability and convenient tests have facilitated their widespread clinical application. Troponins are among the earliest biomarkers identified for detecting cardiac injury. Cardiac troponins are released into the bloodstream when myocardial injury occurs, reflecting structural changes in the myocardium. Studies have demonstrated the predictive value of troponins in anticipating RT-induced cardiotoxicity in the preclinical phase. Skytta et al.33 reported an increase in serum high-sensitivity troponin T (hsTnT) levels in 21 % patients with left-sided breast cancer post-RT, and a correlation was identified between this increase and higher radiation doses. Tao et al.34 also observed significant increases in hsTnT and N-terminal pro-B-type natriuretic peptide levels in 202 patients receiving thoracic RT. This elevation occurred at a median of two months post-RT, preceding electrocardiogram changes. In addition, studies have shown RT-induced increases in serum TnI levels in patients with breast cancer.22,35 Yu et al.36 evaluated early radiation-induced changes in LV function among 47 patients with breast cancer and observed a decrease in median hsTnI concentrations two months post-RT; however, there were no significant changes in systolic or diastolic indices from echocardiography at six months post-RT. Accurately identifying early subclinical cardiac dysfunction via traditional biomarkers thus remains a challenge, necessitating future studies to focus on seeking promising biomarkers for the early and precise diagnosis of RIHD.
2.2.2. Novel biomarkers
Lipopolysaccharide-binding protein plays a role in mediating the inflammatory response by binding to lipopolysaccharides. A single-center study involving 51 patients with breast cancer reported a significant correlation between serum lipopolysaccharide-binding protein levels and diastolic function evaluated three years post-RT, indicating the potential of lipopolysaccharide-binding protein as a useful prognostic parameter.37 Placental growth factor (PGF) belongs to the vascular endothelial growth factor (VEGF) family and can enhance angiogenesis and vascular function. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-β superfamily, is released in response to oxidative stress and inflammation. Following RT completion, patients with lung cancer and lymphoma have been reported to exhibit increased PGF and GDF15 levels as compared to those before RT.38 In another clinical investigation, plasma samples from 350 breast cancer survivors and age-matched women without cancer were analyzed for 92 cardiovascular-related proteins.39 No differentially expressed biomarkers were identified between breast cancer survivors treated with RT alone and the control group. However, Tromp et al.39 found that chemotherapy alone or combined with radiotherapy led to increased levels of inflammatory biomarkers such as growth differentiation factor 15, monocyte chemoattractant protein 1, chemokine (C-X-C motif) ligand 16, and tumor necrosis factor superfamily member 13b, indicative of collagen degradation and activation of matrix metalloproteinases. Further studies are warranted to validate the utility of these biomarkers in predicting RIHD.
Recently, microRNAs (miRNAs) have emerged as potential predictors of RIHD. Increased expression of circulating cardiovascular-related miRNAs (miRNA-146a, miRNA-221, and miRNA-222) has been reported in patients with breast cancer post-RT,40 suggesting a role for miRNAs in mediating RT-related cardiac injury. However, the exact mechanisms remain unclear, necessitating additional studies and clinical data to establish miRNAs as novel biomarkers for detecting RT-induced cardiotoxicity.
3. Therapies
In this section, we review evidence supporting the use of radiation-protective strategies, encompassing traditional clinical cardiac drugs, synthetic drugs, natural products, stem cell therapy, and nanomaterials. Given the scarcity of research data specifically addressing the treatment of RIHD, this section also incorporates findings related to other organ systems or heart diseases caused by different factors to demonstrate the potential efficacy of these approaches in mitigating RIHD. Moreover, it is noteworthy that any treatment aimed at shielding the heart from radiation injury must not impede the response of tumors to radiation. Striking a balance between ensuring adequate heart protection and maintaining effective anticancer treatment is paramount.
3.1. Traditional clinical cardiac drugs
3.1.1. Statins
Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the most effective lipid-lowering drugs available at present.41 Their primary clinical effects include reducing cholesterol levels and lipoprotein density in plasma, mitigating the development of atherosclerosis and cardiotoxicity.42 Statins have been widely reported to modulate oxidative stress by inhibiting reactive oxygen species (ROS) production and reducing the NAD+/NADH ratio, thereby exerting a cardioprotective effect.43 For instance, Zhang et al.44 indicated that atorvastatin could alleviate radiation-induced myocardial fibrosis in rats by reducing the expression of transforming growth factor-β and inhibiting downstream SMAD signaling pathways. Lenarczyk et al.45 reported that simvastatin alleviated increases in risk factors and the occurrence of cardiac disease following 10 Gy total body irradiation (TBI), in addition to improving the ability to withstand stress from myocardial infarction after TBI. Overall, according to in vivo study results, statins exert cardioprotective effects potentially via anti-inflammatory, antifibrotic, and antioxidative mechanisms. In a retrospective cohort study, Boulet et al.46 investigated the role of statins in mitigating vascular complications in 5,718 patients with cancer after RT to the thorax, head, and neck, reporting that statin users (4,166 patients) exhibited a significantly lower incidence of cardiovascular events than non-statin users (1,552 patients). These findings suggest the potential of statins for RIHD treatment or prevention.
3.1.2. Angiotensin-converting enzyme inhibitors (ACEIs)
The renin-angiotensin-aldosterone system maintains plasma sodium concentration, arterial blood pressure, extracellular volume, and cardiac remodeling.47 By inhibiting angiotensin-converting enzyme inhibitors (ACEIs) and kallikrein activity, ACEIs reduce angiotensin II production and bradykinin degradation, inhibit ROS generation, and promote prostaglandin and nitric oxide release, thereby improving vasodilatation and reversing adverse cardiac remodeling.48 ACEIs, considered a first-line treatment for heart failure,49 have been utilized in rodent models to mitigate radiation-induced toxicity in the lung, kidney, brain, and heart. For example, Sharma et al.50 found that lisinopril mitigated pneumonitis in the right lung of adult rats exposed to high-dose fractionated RT by suppressing ACE-expressing lung myeloid cells. Further, in a rat partial-body irradiation model with minimal bone marrow sparing, Fish et al.51 revealed that combining lisinopril with hydration and antibiotics delayed radiation injuries in multiple organs. Lee et al.52 proved that the chronic administration of ramipril to young adult male mice prevented fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. van der Veen et al.53 suggested that treatment with captopril alleviated pleural and pericardial effusion and LV perivascular fibrosis in irradiated rat hearts. Apart from RIHD, ACEIs can reduce cardiotoxicity caused by chemotherapy. Hullin et al.54 reported that enalapril administration conferred protection against cardiac dysfunction and cardiomyocyte atrophy in a mouse model of chronic doxorubicin-induced cardiotoxicity by activating the PI3K/AKT/mTOR pathway and maintaining normal levels of connective tissue growth factor. These preclinical studies highlight the potential of ACEIs in mitigating radiation-induced injuries in various organs. However, further clinical studies are necessary to determine whether ACEIs can serve as a new therapeutic option for patients with clinical and subclinical cardiovascular injury caused by radiation.
3.2. Synthetic drugs
Senescence refers to the irreversible arrest of cell renewal. Radiation induces cardiomyocyte senescence, as evidenced by the staining of senescence-associated β-galactosidase.55 Moreover, radiation contributes to premature endothelial senescence,56 which is implicated in atherosclerosis pathogenesis through increased ROS production and proinflammatory molecule release.57 Radiation-induced cardiac senescence may play a role in RIHD development, suggesting that antisenescence approaches could be promising to protect against RIHD.
Gao et al.58 demonstrated that the small molecule SR9009 effectively inhibited cellular senescence in the livers of radiation-induced senescence mouse models via Nrf2 activation. Apart from Nrf2 signaling, strategies targeting other senescence-related pathways have been explored. Caloric restriction is among the most extensively studied approaches for delaying senescence and prolonging health span.59 During caloric restriction, autophagy is activated, involving enhanced Sirt1 and AMPK and inhibited mTOR signaling.60 Upregulated Sirt1, mediated by miRNA-34a inhibition, plays a key role in preventing radiation-induced cardiomyocyte senescence.61 Further, doxorubicin-related cardiomyocyte toxicity was found to be alleviated by miRNA-199a-3p-mediated antisenescence effects by repressing the senescence-related protein GATA4.62 Another study reported that metformin protects against myocardial ischemia/reperfusion injury and cell pyroptosis via AMPK/NLRP3 inflammasome pathway.63 Metformin has also been reported to reduce radiation-induced cardiac toxicity risk in patients with breast cancer.64 The antisenescence effects of metformin seem to involve autophagy regulation.65 Li et al.66 reported that rapamycin-induced autophagy decreased lipofuscin accumulation and cardiomyocyte senescence in aging rats. In addition, Park et al.67 found that rapamycin attenuated replicative cell senescence and improved cellular function by regulating mTOR and the STAT3/PIM1 axis in human cardiac progenitor cells. While many radioprotective drugs traditionally target scavenging free radicals or antioxidant compounds to neutralize radiation-induced free radicals, developing drugs aimed at antisenescence could offer an alternative strategy for radiation protection.68
3.3. Natural products
The low cost, easy accessibility, and less toxicity of natural products have made them highly promising in managing RIHD.69 Vitamins, polyphenols, flavonoids, and secondary metabolites extracted from plants offer radioprotective benefits by regulating oxidation, DNA repair, inflammation, signaling, and apoptotic pathways.70 Li et al.71 reported that curcumin reversed radiation-induced apoptosis and inflammation in the rat liver through NF-κB pathway inhibition. Boerma et al.72 observed that the combination of pentoxifylline and α-tocopherol had beneficial effects on irradiated rat hearts, leading to improved myocardial fibrosis and LV function. Saada et al.73 showed that grape seed extract significantly reduced radiation-induced oxidative stress in heart tissues, with a marked decline in serum lactate dehydrogenase, creatine kinase, and aspartate aminotransferase activities in irradiated rat models exposed to 5 Gy γ-radiation. Similarly, Malhotra et al.74 suggested that a secondary metabolite N-acetyl-L-tryptophan glucoside prevented radiation-induced apoptosis by increasing the level of various cytokines. However, the protective effects of clinically administered vitamins C and E against cardiovascular diseases remain controversial.75 Epidemiological data indicate that neither vitamins C nor E supplementation reduces the risk of major cardiovascular events among healthy men.76 On the contrary, a high dietary intake of carotenoids, vitamins C, and E from fruits and vegetables has been found to be beneficial in preventing cardiovascular diseases.77 It is likely that multiple antioxidative components in foods are more effective at combating cardiac injury than individual antioxidant supplementation. Furthermore, the variability in the observed efficacy of vitamins C and E across clinical trials may stem from differences in dosing regimens and patient populations.78 Therefore, the clinical applications of natural foods for radiation protection still have a long way to go.
Plant-derived exosome-like nanovesicles have emerged as a new potential therapeutic candidate, showing various advantages such as low molecular weight, high solubility, ability to cross biological barriers, and safety of composition. Our research group has been focusing on exploring the therapeutic effects of Momordica charantia L., a traditional medicine known for its antioxidative properties. Our studies revealed that polysaccharides extracted from M. charantia conferred protection against cerebral ischemia/reperfusion injury by inhibiting the oxidative stress-mediated c-Jun N-terminal kinase 3 signaling pathway.79 Besides, these polysaccharides were found to promote neural stem cell proliferation and differentiation via the SIRT1/β-catenin axis.80,81 Further, we isolated exosome-like nanovesicles from M. charantia and demonstrated their ability to promote cell proliferation, suppress apoptosis, and mitigate DNA damage in irradiated H9C2 cells, and also alleviate myocardial injury in a thoracic radiation mice model.82 Despite these promising findings, the widespread utilization of plant-derived exosome-like nanovesicles requires extensive basic research and clinical trials.
3.4. Stem cell therapy
RIHD is often accompanied by pericarditis, pericardial effusion, and fibrosis, followed by myocardial ischemia and cardiac remodeling.83 These adverse changes are challenging to reverse owing to the limited regenerative capacity of the myocardium.84 Stem cells are primitive cells, with the capacity for infinite proliferation and differentiation. Newly differentiated cells may replace dead cells, maintaining the integrity of damaged tissues. With the increasing interest in stem cell regeneration therapy, stem cell therapy has garnered significant attention for RIHD treatment. In the past two decades, several clinical trials have emphasized the potential of stem cell therapy for treating cardiovascular diseases.85 In 1994, skeletal muscle myoblasts were effectively transplanted into damaged human hearts for the first time.86 Subsequently, several subsets of bone marrow cells were found to be able to differentiate into cardiomyocytes and vascular cells.87 However, the survival rate of transplanted stem cells remained limited, as observed in experiments using bone marrow mononuclear cells.88 In a recent study, cardiomyocytes derived from human embryonic stem cells were injected into permanently ischemic mouse hearts, improving cardiac function by downregulating tumor necrosis factor-α and IL-6 and upregulating IL-10 expression.89 In 2018, a phase I clinical trial (ESCORT) was conducted, involving the implantation of human embryonic stem cell-derived cardiac progenitors embedded into a fibrin matrix for treating patients with severe heart failure.90 Among stem cell types, mesenchymal stem cells (MSCs) have been extensively studied. Derived from various sources such as bone marrow, adipose tissue, umbilical cord, and placental tissue, MSCs exhibit self-renewal and mesodermal differentiation abilities and possess immune regulation and paracrine functions.91 MSC-derived exosomes have shown promise in inhibiting ischemia/reperfusion injury.92,93 MSC transplantation has also proven effective in alleviating radiation-induced myocardial fibrosis and inflammation while enhancing DNA repair through paracrine mechanisms.94 We previously reported the development of synthetic MSCs by loading MSC conditioned medium with poly(lactic-co-glycolic acid), a biodegradable and biocompatible polymer. These synthetic MSCs were found to effectively promote angiogenesis and LV remodeling in a mouse model of myocardial infarction.95 Despite these advancements, stem cell therapy faces challenges, notably treatment-related ethical concerns, difficulties in stem cell preservation and transportation,96 and low retention rates post-delivery into the body,97 all of which require resolution through extensive preclinical and clinical investigations before widespread clinical application for RIHD treatment can be realized.
3.5. Nanomaterials
Nowadays, nanotechnology in medicine is progressively advancing medical diagnosis and treatment. Nanoscale drug delivery offers several advantages, such as targeted delivery to diseased sites, improved drug bioavailability, and the ability to carry diverse functional payloads.98 Due to these properties, nanomaterials have undergone extensive investigation for the therapy and diagnosis of atherosclerosis.99 The potential of nanomaterials for RIHD treatment is being explored. Ganoderma lucidum spore oil (GLSO) extract has antioxidant potential, but its low water solubility hinders its clinical use. Dai et al.100 reported the synthesis of a GLSO@P188/PEG400 nanosystem. The GLSO@P188/- PEG400 nanosystem improved solubility and free radical scavenging capabilities, resulting in enhanced protection against RIHD. Abdel-Magied et al.101 demonstrated that oral delivery of low-dose (10 mg/kg) zinc oxide nanoparticles reversed oxidative stress and inflammation in irradiated rats. In contrast, high-dose zinc oxide nanoparticles (300 mg/kg) exacerbated radiation injury. Besides, novel fluorescent probe materials are rapidly evolving. Xing et al.102 designed and synthesized PCOD585, a small molecule that released carbon monoxide upon ROS/reactive nitrogen species activation. PCOD585 reacted with free radicals H2O2 and OONO−, generating red fluorescence emitted by rhodamine B and releasing carbon monoxide, which formed a complex to reduce Fe2+ levels. The dual action of PCOD585 in scavenging ROS and releasing carbon monoxide synergistically was observed to inhibit iron-mediated nerve cell death, showing therapeutic potential in oxidative stress injury-related diseases.102 The ability of PCOD585 to clear excessive ROS highlights its potential in mitigating radiation-induced cardiotoxicity, as oxidative stress plays a crucial role in RIHD development.
4. Conclusions
RIHD ranks as the second leading cause of long-term morbidity and mortality among patients with cancer. Early prediction and detection of radiation-induced cardiotoxicity are essential for preventing and managing RIHD. The combined use of multimodal imaging systems can enhance the accuracy of identifying abnormalities in cardiac function and structure. Researchers are investigating emerging cardiovascular biomarkers to facilitate RIHD prediction and diagnosis. At present, the molecular and cellular mechanisms underlying RIHD are being extensively investigated to identify effective treatment strategies. In addition to traditional clinical drugs, synthetic drugs, natural products, stem cell therapy, and nanomaterials show promise for RIHD management.
References
1.
Wang KX, Ye C, Yang X, et al. New insights into the understanding of mechanisms of radiation-induced heart disease. Curr Treat Options Oncol. 2023;24(1):12–29. https://doi.org/10.1007/s11864-022-01041-4.
2.
Cheng YJ, Nie XY, Ji CC, et al. Long-term cardiovascular risk after radiotherapy in women with breast cancer. J Am Heart Assoc. 2017;6(5). https://doi.org/10.1161/JAHA.117.005633.
3.
van Nimwegen FA, Schaapveld M, Cutter DJ, et al. Radiation dose-response relationship for risk of coronary heart disease in survivors of hodgkin lymphoma. J Clin Oncol. 2016;34(3):235–243. https://doi.org/10.1200/JCO.2015.63.4444.
4.
Bergom C, Bradley JA, Ng AK, et al. Past, present, and future of radiation-induced cardiotoxicity: refinements in targeting, surveillance, and risk stratification. JACC Cardio Oncol. 2021;3(3):343–359. https://doi.org/10.1016/j.jaccao.2021.06.007.
5.
Filippi AR, Ragona R, Piva C, et al. Optimized volumetric modulated arc therapy versus 3D-CRT for early stage mediastinal Hodgkin lymphoma without axillary involvement: a comparison of second cancers and heart disease risk. Int J Radiat Oncol Biol Phys. 2015;92(1):161–168. https://doi.org/10.1016/j.ijrobp.2015.02.030.
6.
Shimizu Y, Kodama K, Nishi N, et al. Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950–2003. BMJ. 2010;340:b5349. https://doi.org/10.1136/bmj.b5349.
7.
Gillies M, Richardson DB, Cardis E, et al. Mortality from circulatory diseases and other non-cancer outcomes among nuclear workers in France, the United Kingdom and the United States (INWORKS). Radiat Res. 2017;188(3):276–290. https://doi.org/10.1667/RR14608.1.
8.
Sasi SP, Yan X, Zuriaga-Herrero M, et al. Different sequences of fractionated low-dose proton and single iron-radiation-induced divergent biological responses in the heart. Radiat Res. 2017;188(2):191–203. https://doi.org/10.1667/RR14667.1.
9.
van Nimwegen FA, Schaapveld M, Janus CP, et al. Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk. JAMA Intern Med. 2015;175(6):1007–1017. https://doi.org/10.1001/jamainternmed.2015.1180.
10.
Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987–998. https://doi.org/10.1056/NEJMoa1209825.
11.
Piroth MD, Baumann R, Budach W, et al. Heart toxicity from breast cancer radiotherapy: current findings, assessment, and prevention. Strahlenther Onkol. 2019;195(1):1–12. https://doi.org/10.1007/s00066-018-1378-z.
12.
Sarkozy M, Varga Z, Gaspar R, et al. Pathomechanisms and therapeutic opportunities in radiation-induced heart disease: from bench to bedside. Clin Res Cardiol. 2021;110(4):507–531. https://doi.org/10.1007/s00392-021-01809-y.
13.
Wang H, Wei J, Zheng Q, et al. Radiation-induced heart disease: a review of classification, mechanism and prevention. Int J Biol Sci. 2019;15(10):2128–2138. https://doi.org/10.7150/ijbs.35460.
14.
Belzile-Dugas E, Eisenberg MJ. Radiation-induced cardiovascular disease: review of an underrecognized pathology. J Am Heart Assoc. 2021;10(18):e021686. https://doi.org/10.1161/JAHA.121.021686.
15.
Malik SB, Chen N, Parker 3rd RA, et al. Transthoracic echocardiography: pitfalls and limitations as delineated at cardiac CT and MR imaging. Radiographics. 2017;37(2):383–406. https://doi.org/10.1148/rg.2017160105.
16.
Villarraga HR, Herrmann J, Nkomo VT. Cardio-oncology: role of echocardiography. Prog Cardiovasc Dis. 2014;57(1):10–18. https://doi.org/10.1016/j.pcad.2014.05.002.
17.
Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131(22):1981–1988. https://doi.org/10.1161/CIRCULATIONAHA.114.013777.
18.
Thavendiranathan P, Negishi T, Somerset E, et al. Strain-guided management of potentially cardiotoxic cancer therapy. J Am Coll Cardiol. 2021;77(4):392–401. https://doi.org/10.1016/j.jacc.2020.11.020.
19.
Esmaeilzadeh M, Urzua Fresno CM, Somerset E, et al. A combined echocardiography approach for the diagnosis of cancer therapy-related cardiac dysfunction in women with early-stage breast cancer. JAMA Cardiol. 2022;7(3):330–340. https://doi.org/10.1001/jamacardio.2021.5881.
20.
Walker J, Bhullar N, Fallah-Rad N, et al. Role of three-dimensional echocardiography in breast cancer: comparison with two-dimensional echocardiography, multiple-gated acquisition scans, and cardiac magnetic resonance imaging. J Clin Oncol. 2010;28(21):3429–3436. https://doi.org/10.1200/JCO.2009.26.7294.
21.
Bian SX, Korah MP, Whitaker TR, et al. No acute changes in lvef observed with concurrent trastuzumab and breast radiation with low heart doses. Clin Breast Cancer. 2017;17(7):510–515. https://doi.org/10.1016/j.clbc.2017.03.011.
22.
Erven K, Florian A, Slagmolen P, et al. Subclinical cardiotoxicity detected by strain rate imaging up to 14 months after breast radiation therapy. Int J Radiat Oncol Biol Phys. 2013;85(5):1172–1178. https://doi.org/10.1016/j.ijrobp.2012.09.022.
23.
Curigliano G, Cardinale D, Dent S, et al. Cardiotoxicity of anticancer treatments: epidemiology, detection, and management. CA Cancer J Clin. 2016;66(4):309–325. https://doi.org/10.3322/caac.21341.
24.
Tsai HR, Gjesdal O, Wethal T, et al. Left ventricular function assessed by two-dimensional speckle tracking echocardiography in long-term survivors of Hodgkin’s lymphoma treated by mediastinal radiotherapy with or without anthracycline therapy. Am J Cardiol. 2011;107(3):472–477. https://doi.org/10.1016/j.amjcard.2010.09.048.
25.
Speers C, Murthy VL, Walker EM, et al. Cardiac magnetic resonance imaging and blood biomarkers for evaluation of radiation-induced cardiotoxicity in patients with breast cancer: results of a phase 2 clinical trial. Int J Radiat Oncol Biol Phys. 2022;112(2):417–425. https://doi.org/10.1016/j.ijrobp.2021.08.039.
26.
Machann W, Beer M, Breunig M, et al. Cardiac magnetic resonance imaging findings in 20-year survivors of mediastinal radiotherapy for Hodgkin’s disease. Int J Radiat Oncol Biol Phys. 2011;79(4):1117–1123. https://doi.org/10.1016/j.ijrobp.2009.12.054.
27.
Beukema JC, de Groot C, Plukker JTM, et al. Late cardiac toxicity of neo-adjuvant chemoradiation in esophageal cancer survivors: a prospective cross-sectional pilot study. Radiother Oncol. 2022;167:72–77. https://doi.org/10.1016/j.radonc.2021.11.029.
28.
Takagi H, Ota H, Umezawa R, et al. Left ventricular t1 mapping during chemotherapy-radiation therapy: serial assessment of participants with esophageal cancer. Radiology. 2018;289(2):347–354. https://doi.org/10.1148/radiol.2018172076.
29.
Zhang P, Hu X, Yue J, et al. Early detection of radiation-induced heart disease using (99m)Tc-MIBI SPECT gated myocardial perfusion imaging in patients with oesophageal cancer during radiotherapy. Radiother Oncol. 2015;115(2):171–178. https://doi.org/10.1016/j.radonc.2015.04.009.
30.
Cuomo JR, Javaheri SP, Sharma GK, et al. How to prevent and manage radiation-induced coronary artery disease. Heart. 2018;104(20):1647–1653. https://doi.org/10.1136/heartjnl-2017-312123.
31.
Girinsky T, M’Kacher R, Lessard N, et al. Prospective coronary heart disease screening in asymptomatic Hodgkin lymphoma patients using coronary computed tomography angiography: results and risk factor analysis. Int J Radiat Oncol Biol Phys. 2014;89(1):59–66. https://doi.org/10.1016/j.ijrobp.2014.01.021.
32.
Wei Y, Sun Y, Liu J, et al. Early detection of radiation-induced myocardial damage by [(18)F]AlF-NOTA-FAPI-04 PET/CT imaging. Eur J Nucl Med Mol Imag. 2023;50(2):453–464. https://doi.org/10.1007/s00259-022-05962-y.
33.
Skytta T, Tuohinen S, Boman E, et al. Troponin T-release associates with cardiac radiation doses during adjuvant left-sided breast cancer radiotherapy. Radiat Oncol. 2015;10:141. https://doi.org/10.1186/s13014-015-0436-2.
34.
Tao Y, Lu J, Deng W, et al. Correlation of mean heart dose and cardiac biomarkers with electrocardiographic changes in patients receiving thoracic radiation therapy. Radiat Res. 2023;199(4):336–345. https://doi.org/10.1667/RADE-22-00135.1.
35.
Ky B, Putt M, Sawaya H, et al. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol. 2014;63(8):809–816. https://doi.org/10.1016/j.jacc.2013.10.061.
36.
Yu AF, Ho AY, Braunstein LZ, et al. Assessment of early radiation-induced changes in left ventricular function by myocardial strain imaging after breast radiation therapy. J Am Soc Echocardiogr. 2019;32(4):521–528. https://doi.org/10.1016/j.echo.2018.12.009.
37.
Chalubinska-Fendler J, Graczyk L, Piotrowski G, et al. Lipopolysaccharide-binding protein is an early biomarker of cardiac function after radiation therapy for breast cancer. Int J Radiat Oncol Biol Phys. 2019;104(5):1074–1083. https://doi.org/10.1016/j.ijrobp.2019.04.002.
38.
Demissei BG, Freedman G, Feigenberg SJ, et al. Early changes in cardiovascular biomarkers with contemporary thoracic radiation therapy for breast cancer, lung cancer, and lymphoma. Int J Radiat Oncol Biol Phys. 2019;103(4):851–860. https://doi.org/10.1016/j.ijrobp.2018.11.013.
39.
Tromp J, Boerman LM, Sama IE, et al. Long-term survivors of early breast cancer treated with chemotherapy are characterized by a pro-inflammatory biomarker profile compared to matched controls. Eur J Heart Fail. 2020;22(7):1239–1246. https://doi.org/10.1002/ejhf.1758.
40.
Esplugas R, Arenas M, Serra N, et al. Effect of radiotherapy on the expression of cardiovascular disease-related miRNA-146a, -155, -221 and -222 in blood of women with breast cancer. PLoS One. 2019;14(5):e0217443. https://doi.org/10.1371/journal.pone.0217443.
41.
Liu A, Wu Q, Guo J, et al. Statins: adverse reactions, oxidative stress and metabolic interactions. Pharmacol Ther. 2019;195:54–84. https://doi.org/10.1016/j.pharmthera.2018.10.004.
42.
Lee MMY, Sattar N, McMurray JJV, et al. Statins in the prevention and treatment of heart failure: a review of the evidence. Curr Atherosclerosis Rep. 2019;21(10):41. https://doi.org/10.1007/s11883-019-0800-z.
43.
Lim S, Barter P. Antioxidant effects of statins in the management of cardiometabolic disorders. J Atherosclerosis Thromb. 2014;21(10):997–1010. https://doi.org/10.5551/jat.24398.
44.
Zhang K, He X, Zhou Y, et al. Atorvastatin ameliorates radiation-induced cardiac fibrosis in rats. Radiat Res. 2015;184(6):611–620. https://doi.org/10.1667/RR14075.1.
45.
Lenarczyk M, Su J, Haworth ST, et al. Simvastatin mitigates increases in risk factors for and the occurrence of cardiac disease following 10 Gy total body irradiation. Pharmacol Res Perspect. 2015;3(3):e00145. https://doi.org/10.1002/prp2.145.
46.
Boulet J, Pena J, Hulten EA, et al. Statin use and risk of vascular events among cancer patients after radiotherapy to the thorax, head, and neck. J Am Heart Assoc. 2019;8(13):e005996. https://doi.org/10.1161/JAHA.117.005996.
47.
Patel S, Rauf A, Khan H, et al. Renin-angiotensin-aldosterone (RAAS): the ubiquitous system for homeostasis and pathologies. Biomed Pharmacother. 2017;94:317–325. https://doi.org/10.1016/j.biopha.2017.07.091.
48.
Bertrand ME. Provision of cardiovascular protection by ACE inhibitors: a review of recent trials. Curr Med Res Opin. 2004;20(10):1559–1569. https://doi.org/10.1185/030079904X4185.
49.
Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: a report of the american college of cardiology/american heart association joint committee on clinical practice guidelines. Circulation. 2022;145(18):e876–e894. https://doi.org/10.1161/CIR.0000000000001062.
50.
Sharma GP, Fish BL, Frei AC, et al. Pharmacologic ACE-inhibition mitigates radiation-induced pneumonitis by suppressing ace-expressing lung myeloid cells. Int J Radiat Oncol Biol Phys. 2022;113(1):177–191. https://doi.org/10.1016/j.ijrobp.2022.01.023.
51.
Fish BL, Gao F, Narayanan J, et al. Combined hydration and antibiotics with lisinopril to mitigate acute and delayed high-dose radiation injuries to multiple organs. Health Phys. 2016;111(5):410–419. https://doi.org/10.1097/HP.0000000000000554.
52.
Lee TC, Greene-Schloesser D, Payne V, et al. Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Radiat Res. 2012;178(1):46–56. https://doi.org/10.1667/rr2731.1.
53.
van der Veen SJ, Ghobadi G, de Boer RA, et al. ACE inhibition attenuates radiation-induced cardiopulmonary damage. Radiother Oncol. 2015;114(1):96–103. https://doi.org/10.1016/j.radonc.2014.11.017.
54.
Hullin R, Metrich M, Sarre A, et al. Diverging effects of enalapril or eplerenone in primary prevention against doxorubicin-induced cardiotoxicity. Cardiovasc Res. 2018;114(2):272–281. https://doi.org/10.1093/cvr/cvx162.
55.
Kim EJ, Lee J, Jung YR, et al. Involvement of corin downregulation in ionizing radiation-induced senescence of myocardial cells. Int J Mol Med. 2015;35(3):731–738. https://doi.org/10.3892/ijmm.2014.2048.
56.
Yentrapalli R, Azimzadeh O, Barjaktarovic Z, et al. Quantitative proteomic analysis reveals induction of premature senescence in human umbilical vein endothelial cells exposed to chronic low-dose rate gamma radiation. Proteomics. 2013;13(7):1096–1107. https://doi.org/10.1002/pmic.201200463.
57.
Baselet B, Sonveaux P, Baatout S, et al. Pathological effects of ionizing radiation: endothelial activation and dysfunction. Cell Mol Life Sci. 2019;76(4):699–728. https://doi.org/10.1007/s00018-018-2956-z.
58.
Gao LB, Wang YH, Liu ZH, et al. Identification of a small molecule SR9009 that activates NRF2 to counteract cellular senescence. Aging Cell. 2021;20(10):e13483. https://doi.org/10.1111/acel.13483.
59.
Madeo F, Carmona-Gutierrez D, Hofer SJ, et al. Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential. Cell Metabol. 2019;29(3):592–610. https://doi.org/10.1016/j.cmet.2019.01.018.
60.
Abdelgawad IY, Sadak KT, Lone DW, et al. Molecular mechanisms and cardiovascular implications of cancer therapy-induced senescence. Pharmacol Ther. 2021;221:107751. https://doi.org/10.1016/j.pharmthera.2020.107751.
61.
Hu Y, Xia W, Hou M. Macrophage migration inhibitory factor serves a pivotal role in the regulation of radiation-induced cardiac senescencethrough rebalancing the microRNA-34a/sirtuin 1 signaling pathway. Int J Mol Med. 2018;42(5):2849–2858. https://doi.org/10.3892/ijmm.2018.3838.
62.
Xia W, Chang B, Li L, et al. MicroRNA therapy confers anti-senescent effects on doxorubicin-related cardiotoxicity by intracellular and paracrine signaling. Aging (Albany NY). 2021;13(23):25256–25270. https://doi.org/10.18632/aging.203743.
63.
Zhang J, Huang L, Shi X, et al. Metformin protects against myocardial ischemia-reperfusion injury and cell pyroptosis via AMPK/NLRP3 inflammasome pathway. Aging (Albany NY). 2020;12(23):24270–24287. https://doi.org/10.18632/aging.202143.
64.
Yu JM, Hsieh MC, Qin L, et al. Metformin reduces radiation-induced cardiac toxicity risk in patients having breast cancer. Am J Cancer Res. 2019;9(5):1017–1026.
65.
Lu G, Wu Z, Shang J, et al. The effects of metformin on autophagy. Biomed Pharmacother. 2021;137:111286. https://doi.org/10.1016/j.biopha.2021.111286.
66.
Li WW, Wang HJ, Tan YZ, et al. Reducing lipofuscin accumulation and cardiomyocytic senescence of aging heart by enhancing autophagy. Exp Cell Res. 2021;403(1):112585. https://doi.org/10.1016/j.yexcr.2021.112585.
67.
Park JH, Lee NK, Lim HJ, et al. Pharmacological inhibition of mTOR attenuates replicative cell senescence and improves cellular function via regulating the STAT3-PIM1 axis in human cardiac progenitor cells. Exp Mol Med. 2020;52(4):615–628. https://doi.org/10.1038/s12276-020-0374-4.
68.
Nagane M, Yasui H, Kuppusamy P, et al. DNA damage response in vascular endothelial senescence: implication for radiation-induced cardiovascular diseases. J Radiat Res. 2021;62(4):564–573. https://doi.org/10.1093/jrr/rrab032.
69.
Yi J, Zhu J, Zhao C, et al. Potential of natural products as radioprotectors and radiosensitizers: opportunities and challenges. Food Funct. 2021;12(12):5204–5218. https://doi.org/10.1039/d1fo00525a.
70.
Mun GI, Kim S, Choi E, et al. Pharmacology of natural radioprotectors. Arch Pharm Res (Seoul). 2018;41(11):1033–1050. https://doi.org/10.1007/s12272-018-1083-6.
71.
Li W, Jiang L, Lu X, et al. Curcumin protects radiation-induced liver damage in rats through the NF-kappaB signaling pathway. BMC Complement Med Ther. 2021;21(1):10. https://doi.org/10.1186/s12906-020-03182-1.
72.
Boerma M, Roberto KA, Hauer-Jensen M. Prevention and treatment of functional and structural radiation injury in the rat heart by pentoxifylline and alpha-tocopherol. Int J Radiat Oncol Biol Phys. 2008;72(1):170–177. https://doi.org/10.1016/j.ijrobp.2008.04.042.
73.
Saada HN, Said UZ, Meky NH, et al. Grape seed extract Vitis vinifera protects against radiation-induced oxidative damage and metabolic disorders in rats. Phytother Res. 2009;23(3):434–438. https://doi.org/10.1002/ptr.2684.
74.
Malhotra P, Adhikari M, Singh SK, et al. N-acetyl tryptophan glucopyranoside (NATG) provides radioprotection to murine macrophage J774A.1 cells. Free Radic Res. 2015;49(12):1488–1498. https://doi.org/10.3109/10715762.2015.1095295.
75.
Mitu O, Cirneala IA, Lupsan AI, et al. The Effect of vitamin supplementation on subclinical atherosclerosis in patients without manifest cardiovascular diseases: never-ending hope or underestimated effect? Molecules. 2020;25(7). https://doi.org/10.3390/molecules25071717.
76.
Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the physicians' health study II randomized controlled trial. JAMA. 2008;300(18):2123–2133. https://doi.org/10.1001/jama.2008.600.
77.
Aune D, Keum N, Giovannucci E, et al. Dietary intake and blood concentrations of antioxidants and the risk of cardiovascular disease, total cancer, and all-cause mortality: a systematic review and dose-response meta-analysis of prospective studies. Am J Clin Nutr. 2018;108(5):1069–1091. https://doi.org/10.1093/ajcn/nqy097.
78.
Riccioni G, D’Orazio N, Salvatore C, et al. Carotenoids and vitamins C and E in the prevention of cardiovascular disease. Int J Vitam Nutr Res. 2012;82(1):15–26. https://doi.org/10.1024/0300-9831/a000090.
79.
Gong J, Sun F, Li Y, et al. Momordica charantia polysaccharides could protect against cerebral ischemia/reperfusion injury through inhibiting oxidative stress mediated c-Jun N-terminal kinase 3 signaling pathway. Neuropharmacology. 2015;91:123–134. https://doi.org/10.1016/j.neuropharm.2014.11.020.
80.
Ma J, Fan H, Cai H, et al. Promotion of Momordica Charantia polysaccharides on neural stem cell proliferation by increasing SIRT1 activity after cerebral ischemia/reperfusion in rats. Brain Res Bull. 2021;170:254–263. https://doi.org/10.1016/j.brainresbull.2021.02.016.
81.
Hu Z, Li F, Zhou X, et al. Momordica charantia polysaccharides modulate the differentiation of neural stem cells via SIRT1/Beta-catenin axis in cerebral ischemia/reperfusion. Stem Cell Res Ther. 2020;11(1):485. https://doi.org/10.1186/s13287-020-02000-2.
82.
Cui WW, Ye C, Wang KX, et al. Momordica. charantia-derived extracellular vesicles-like nanovesicles protect cardiomyocytes against radiation injury via attenuating DNA damage and mitochondria dysfunction. Front Cardiovasc Med. 2022;9:864188. https://doi.org/10.3389/fcvm.2022.864188.
83.
Steiner I. Pathology of radiation induced heart disease. Rep Practical Oncol Radiother. 2020;25(2):178–181. https://doi.org/10.1016/j.rpor.2019.12.015.
84.
Tzahor E, Poss KD. Cardiac regeneration strategies: staying young at heart. Science. 2017;356(6342):1035–1039. https://doi.org/10.1126/science.aam5894.
85.
Muller P, Lemcke H, David R. Stem cell therapy in heart diseases - cell types, mechanisms and improvement strategies. Cell Physiol Biochem. 2018;48(6):2607–2655. https://doi.org/10.1159/000492704.
86.
Zibaitis A, Greentree D, Ma F, et al. Myocardial regeneration with satellite cell implantation. Transplant Proc. 1994;26(6):3294.
87.
Collins SD, Baffour R, Waksman R. Cell therapy in myocardial infarction. Cardiovasc Revascularization Med. 2007;8(1):43–51. https://doi.org/10.1016/j.carrev.2006.11.005.
88.
Sano T, Ishigami S, Ito T, et al. Stem cell therapy in heart disease: limitations and future possibilities. Acta Med Okayama. 2020;74(3):185–190. https://doi.org/10.18926/AMO/59948.
89.
Yu Y, Qin N, Lu XA, et al. Human embryonic stem cell-derived cardiomyocyte therapy in mouse permanent ischemia and ischemia-reperfusion models. Stem Cell Res Ther. 2019;10(1):167. https://doi.org/10.1186/s13287-019-1271-4.
90.
Menasche P, Vanneaux V, Hagege A, et al. Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. J Am Coll Cardiol. 2018;71(4):429–438. https://doi.org/10.1016/j.jacc.2017.11.047.
91.
Wang KX, Cui WW, Yang X, et al. Mesenchymal stem cells for mitigating radiotherapy side effects. Cells. 2021;10(2). https://doi.org/10.3390/cells10020294.
92.
Zou L, Ma X, Wu B, et al. Protective effect of bone marrow mesenchymal stem cell-derived exosomes on cardiomyoblast hypoxia-reperfusion injury through the miR-149/let-7c/Faslg axis. Free Radic Res. 2020;54(10):722–731. https://doi.org/10.1080/10715762.2020.1837793.
93.
Wang X, Bai L, Liu X, et al. Cardiac microvascular functions improved by MSC-derived exosomes attenuate cardiac fibrosis after ischemia-reperfusion via PDGFR-beta modulation. Int J Cardiol. 2021;344:13–24. https://doi.org/10.1016/j.ijcard.2021.09.017.
94.
Gao S, Zhao Z, Wu R, et al. Bone marrow mesenchymal stem cell transplantation improves radiation-induced heart injury through DNA damage repair in rat model. Radiat Environ Biophys. 2017;56(1):63–77. https://doi.org/10.1007/s00411-016-0675-0.
95.
Luo L, Tang J, Nishi K, et al. Fabrication of synthetic mesenchymal stem cells for the treatment of acute myocardial infarction in mice. Circ Res. 2017;120(11):1768–1775. https://doi.org/10.1161/CIRCRESAHA.116.310374.
96.
Wragg NM, Tampakis D, Stolzing A. Cryopreservation of mesenchymal stem cells using medical grade ice nucleation inducer. Int J Mol Sci. 2020;21(22). https://doi.org/10.3390/ijms21228579.
97.
Guo Y, Yu Y, Hu S, et al. The therapeutic potential of mesenchymal stem cells for cardiovascular diseases. Cell Death Dis. 2020;11(5):349. https://doi.org/10.1038/s41419-020-2542-9.
98.
Park JH, Dehaini D, Zhou J, et al. Biomimetic nanoparticle technology for cardiovascular disease detection and treatment. Nanoscale Horiz. 2020;5(1):25–42. https://doi.org/10.1039/c9nh00291j.
99.
Chen J, Zhang X, Millican R, et al. Recent advances in nanomaterials for therapy and diagnosis for atherosclerosis. Adv Drug Deliv Rev. 2021;170:142–199. https://doi.org/10.1016/j.addr.2021.01.005.
100.
Dai C, He L, Ma B, et al. Facile nanolization strategy for therapeutic ganoderma lucidum spore oil to achieve enhanced protection against radiation-induced heart disease. Small. 2019;15(36):e1902642. https://doi.org/10.1002/smll.201902642.
101.
Abdel-Magied N, Shedid SM. Impact of zinc oxide nanoparticles on thioredoxin-interacting protein and asymmetric dimethylarginine as biochemical indicators of cardiovascular disorders in gamma-irradiated rats. Environ Toxicol. 2020;35(4):430–442. https://doi.org/10.1002/tox.22879.
102.
Xing L, Wang B, Li J, et al. A fluorogenic ONOO(-)-triggered carbon monoxide donor for mitigating brain ischemic damage. J Am Chem Soc. 2022;144(5):2114–2119. https://doi.org/10.1021/jacs.2c00094.
Information & Authors
Information
Published In
Radiation Medicine and Protection
Volume 05 • Number 02 • 30 June 2024
Pages: 83 - 89
Copyright
© 2024 Chinese Medical Association. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CC BY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
History
Received: 29 February 2024
Revision received: 26 April 2024
Accepted: 26 April 2024
Published online: 30 April 2024
Keywords
Authors
Declaration of Competing Interest
None.
Funding Information
National Natural Science Foundation of China: No. 82270360
Natural Science Foundation of Jiangsu Province: No. BK20231183
Project of Science and Technology Department of Jiangxi Province: No. 20204BCJ23018
the Young Science and Technology Innovation Team of Xuzhou Medical University, China.
Metrics & Citations
Metrics
Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.