Modern Radiotherapy and Risk of Cardiotoxicity

Koutroumpakis, Efstratios; Palaskas, Nicolas; Lin, Steven H.; Abe, Jun; Liao, Zhongxing; Banchs, José; Deswal, Anita; Yusuf, Syed Wamique

doi:10.1159/000510573

Cited by 33 publications

(42 citation statements)

References 94 publications

(148 reference statements)

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“…Radiotherapy to the chest in contrast induces chronic excess secretion of interleukins IL-6 and IL-8, potentially manifesting adverse late effects in the heart [46]. These interleukins are predominantly released by endothelial cells as mediators of subsequent inflammatory processes [47], but also CM are involved in pro-inflammatory signaling. IL-6 and IL-8 are apparent in the myocardium mediating acute inflammation formation [28] and hPSC-CM in vitro responded to ischemic conditions with increased levels of IL-6 and IL-8 similar to observations in vivo [28].…”

Section: Discussionmentioning

confidence: 99%

A Human 3D Cardiomyocyte Risk Model to Study the Cardiotoxic Influence of X-rays and Other Noxae in Adults

Smit

Schickel

Azimzadeh

et al. 2021

Cells

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The heart tissue is a potential target of various noxae contributing to the onset of cardiovascular diseases. However, underlying pathophysiological mechanisms are largely unknown. Human stem cell-derived models are promising, but a major concern is cell immaturity when estimating risks for adults. In this study, 3D aggregates of human embryonic stem cell-derived cardiomyocytes were cultivated for 300 days and characterized regarding degree of maturity, structure, and cell composition. Furthermore, effects of ionizing radiation (X-rays, 0.1–2 Gy) on matured aggregates were investigated, representing one of the noxae that are challenging to assess. Video-based functional analyses were correlated to changes in the proteome after irradiation. Cardiomyocytes reached maximum maturity after 100 days in cultivation, judged by α-actinin lengths, and displayed typical multinucleation and branching. At this time, aggregates contained all major cardiac cell types, proven by the patch-clamp technique. Matured and X-ray-irradiated aggregates revealed a subtle increase in beat rates and a more arrhythmic sequence of cellular depolarisation and repolarisation compared to non-irradiated sham controls. The proteome analysis provides first insights into signaling mechanisms contributing to cardiotoxicity. Here, we propose an in vitro model suitable to screen various noxae to target adult cardiotoxicity by preserving all the benefits of a 3D tissue culture.

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Section: Discussionmentioning

confidence: 99%

A Human 3D Cardiomyocyte Risk Model to Study the Cardiotoxic Influence of X-rays and Other Noxae in Adults

Smit

Schickel

Azimzadeh

et al. 2021

Cells

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“…The node corresponding to the gene HMOX1 (heme oxygenase 1) is the most highly connected to the non-neoplastic diseases (Figure 2). HMOX1 and TNF (tumor necrosis factor) are associated with several diseases of diverse tissue origin, quite a few of which are also suggested to be linked to the adverse effects of RT, like cardiovascular diseases [46,47], colitis [48], diseases related to blood glucose, status epilepticus, kidney [44,45] and liver [49] diseases (Figure 2).…”

Section: Associations Among Genes Cancers and Non-neoplastic Diseasesmentioning

confidence: 99%

In Silico Investigation of the Biological Implications of Complex DNA Damage with Emphasis in Cancer Radiotherapy through a Systems Biology Approach

et al. 2021

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Different types of DNA lesions forming in close vicinity, create clusters of damaged sites termed as “clustered/complex DNA damage” and they are considered to be a major challenge for DNA repair mechanisms resulting in significant repair delays and induction of genomic instability. Upon detection of DNA damage, the corresponding DNA damage response and repair (DDR/R) mechanisms are activated. The inability of cells to process clustered DNA lesions efficiently has a great impact on the normal function and survival of cells. If complex lesions are left unrepaired or misrepaired, they can lead to mutations and if persistent, they may lead to apoptotic cell death. In this in silico study, and through rigorous data mining, we have identified human genes that are activated upon complex DNA damage induction like in the case of ionizing radiation (IR) and beyond the standard DNA repair pathways, and are also involved in cancer pathways, by employing stringent bioinformatics and systems biology methodologies. Given that IR can cause repair resistant lesions within a short DNA segment (a few nm), thereby augmenting the hazardous and toxic effects of radiation, we also investigated the possible implication of the most biologically important of those genes in comorbid non-neoplastic diseases through network integration, as well as their potential for predicting survival in cancer patients.

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“…Radiation induces DNA damage, oxidative stress, endothelial cell senescence, and pro-inflammatory pathways. These changes may result in intimal thickening, fibrin deposition, lipid accumulation, and thrombosis [ 37 ]. In the acute time period, pericarditis and myocarditis may be observed; however, their incidence is low with modern RT.…”

Section: Pathophysiology Of Cardiotoxic Cancer Therapiesmentioning

confidence: 99%

“…In the acute time period, pericarditis and myocarditis may be observed; however, their incidence is low with modern RT. Late effects, such as coronary artery disease (CAD), valvular disease, restrictive cardiomyopathy, and arrhythmias may become apparent years or decades after RT [ 37 , 38 ]. Importantly, the age at onset of late effects is variable and depends in part on the patient’s age when cancer therapy commenced.…”

Section: Pathophysiology Of Cardiotoxic Cancer Therapiesmentioning

confidence: 99%

Mechanisms and Insights for the Development of Heart Failure Associated with Cancer Therapy

et al. 2021

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Cardiotoxicity is a well-recognized late effect among childhood cancer survivors. With various pediatric cancers becoming increasingly curable, it is imperative to understand the disease burdens that survivors may face in the future. In order to prevent or mitigate cardiovascular complications, we must first understand the mechanistic underpinnings. This review will examine the underlying mechanisms of cardiotoxicity that arise from traditional antineoplastic chemotherapies, radiation therapy, hematopoietic stem cell transplantation, as well as newer cellular therapies and targeted cancer therapies. We will then propose areas for prevention, primarily drawing from the anthracycline-induced cardiotoxicity literature. Finally, we will explore the role of human induced pluripotent stem cell cardiomyocytes and genetics in advancing the field of cardio-oncology.

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Modern Radiotherapy and Risk of Cardiotoxicity

Cited by 33 publications

References 94 publications

A Human 3D Cardiomyocyte Risk Model to Study the Cardiotoxic Influence of X-rays and Other Noxae in Adults

A Human 3D Cardiomyocyte Risk Model to Study the Cardiotoxic Influence of X-rays and Other Noxae in Adults

In Silico Investigation of the Biological Implications of Complex DNA Damage with Emphasis in Cancer Radiotherapy through a Systems Biology Approach

Mechanisms and Insights for the Development of Heart Failure Associated with Cancer Therapy

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