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Title:
Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients | Basic Research in Cardiology
Description:
Cancer therapies with anthracyclines have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of B-cell lymphoma and to examine whether doxorubicin (DOX)-treated ACT-iPSC cardiomyocytes (CM) can recapitulate the clinical features exhibited by patients, and thus help uncover a DOX-dependent pathomechanism. ACT-iPSC CM generated from individuals with CD20+ B-cell lymphoma who had received high doses of DOX and suffered cardiac dysfunction were studied and compared to control-iPSC CM from cancer survivors without cardiac symptoms. In cellular studies, ACT-iPSC CM were persistently more susceptible to DOX toxicity including augmented disorganized myofilament structure, changed mitochondrial shape, and increased apoptotic events. Consistently, ACT-iPSC CM and cardiac fibroblasts isolated from fibrotic human ACT myocardium exhibited higher DOX-dependent reactive oxygen species. In functional studies, Ca2+ transient amplitude of ACT-iPSC CM was reduced compared to control cells, and diastolic sarcoplasmic reticulum Ca2+ leak was DOX-dependently increased. This could be explained by overactive CaMKIIδ in ACT CM. Together with DOX-dependent augmented proarrhythmic cellular triggers and prolonged action potentials in ACT CM, this suggests a cellular link to arrhythmogenic events and contractile dysfunction especially found in ACT engineered human myocardium. CamKIIδ inhibition prevented proarrhythmic triggers in ACT. In contrast, control CM upregulated SERCA2a expression in a DOX-dependent manner, possibly to avoid heart failure conditions. In conclusion, we developed the first human patient-specific stem cell model of DOX-induced cardiac dysfunction from patients with B-cell lymphoma. Our results suggest that DOX-induced stress resulted in arrhythmogenic events associated with contractile dysfunction and finally in heart failure after persistent stress activation in ACT patients.
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Keywords {🔍}
act, dox, patients, control, fig, ipsc, cardiac, article, treatment, ehm, cell, patient, google, scholar, human, analysis, cas, cells, expression, compared, doxdependent, supplementary, heart, increased, cardiotoxicity, actipsc, significantly, mitochondrial, myocardium, data, study, dysfunction, doxinduced, performed, stem, failure, controls, cfb, found, untreated, camkiiδ, analyzed, lines, germany, genes, göttingen, differentiations, cardiomyocytes, sercaa, conditions,
Topics {✒️}
kröner-fresenius-stiftung foundation [2017-a137] catecholamine-dependent beta-adrenergic signaling gov/ij/plugins/radial-profile modulating wnt/beta-catenin signaling act-specific dox-dependent degs pressure-induced heart disease katrin streckfuss-bömeke modeling doxorubicin-induced cardiotoxicity human ipsc-derived cardiomyocytes end-stage heart failure inducible cardiomyocyte-specific deletion dhe-derived oxidation products highly inter-individually variable act-ipsc cm exhibited peltier-cooled xc10 camera article download pdf patient-specific model system pre-cooled cardioplegic solution kos/hc-myc/hklf4 end-stage act myocardium trastuzumab-induced cardiac dysfunction dose-dependent relative increase increased dox-dependent apoptosis dox-induced heart failure pbpk-based dose modelling dox dose-dependent manner dox-dependent upregulated degs inherently immature ipsc-derivatives patient-specific gene expression cell patch-clamp technique chronic cardiotoxicity model α-myosin heavy chain patient-specific ipsc model cd20+ b-cell lymphoma cd20 + b-cell lymphoma dox-induced cardiac dysfunction nhl-b1/b2 study cardiac marker α-actinin patient-specific act model dox concentration-dependent manner dox-induced cell loss dox-dependent ros production potential cardio-protective mechanisms dox-induced stress resulted human cardiomyocytes derived β-myosin heavy chain dox-induced relative change 5 ng/ml tgf-b1 stem cell model patient-specific ipsc cm
Questions {❓}
- Magdy T, Burmeister BT, Burridge PW (2016) Validating the pharmacogenomics of chemotherapy-induced cardiotoxicity: What is missing?
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headline:Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients
description:Cancer therapies with anthracyclines have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of B-cell lymphoma and to examine whether doxorubicin (DOX)-treated ACT-iPSC cardiomyocytes (CM) can recapitulate the clinical features exhibited by patients, and thus help uncover a DOX-dependent pathomechanism. ACT-iPSC CM generated from individuals with CD20+ B-cell lymphoma who had received high doses of DOX and suffered cardiac dysfunction were studied and compared to control-iPSC CM from cancer survivors without cardiac symptoms. In cellular studies, ACT-iPSC CM were persistently more susceptible to DOX toxicity including augmented disorganized myofilament structure, changed mitochondrial shape, and increased apoptotic events. Consistently, ACT-iPSC CM and cardiac fibroblasts isolated from fibrotic human ACT myocardium exhibited higher DOX-dependent reactive oxygen species. In functional studies, Ca2+ transient amplitude of ACT-iPSC CM was reduced compared to control cells, and diastolic sarcoplasmic reticulum Ca2+ leak was DOX-dependently increased. This could be explained by overactive CaMKIIδ in ACT CM. Together with DOX-dependent augmented proarrhythmic cellular triggers and prolonged action potentials in ACT CM, this suggests a cellular link to arrhythmogenic events and contractile dysfunction especially found in ACT engineered human myocardium. CamKIIδ inhibition prevented proarrhythmic triggers in ACT. In contrast, control CM upregulated SERCA2a expression in a DOX-dependent manner, possibly to avoid heart failure conditions. In conclusion, we developed the first human patient-specific stem cell model of DOX-induced cardiac dysfunction from patients with B-cell lymphoma. Our results suggest that DOX-induced stress resulted in arrhythmogenic events associated with contractile dysfunction and finally in heart failure after persistent stress activation in ACT patients.
datePublished:2022-03-08T00:00:00Z
dateModified:2022-03-08T00:00:00Z
pageStart:1
pageEnd:24
license:http://creativecommons.org/licenses/by/4.0/
sameAs:https://doi.org/10.1007/s00395-022-00918-7
keywords:
Anthracyclin-induced cardiotoxicity (ACT)
Induced pluripotent stem cells (iPSC)
Cardiomyocytes
Cardiac fibroblasts
Heart failure
Doxorubicin
Cardiology
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headline:Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients
description:Cancer therapies with anthracyclines have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of B-cell lymphoma and to examine whether doxorubicin (DOX)-treated ACT-iPSC cardiomyocytes (CM) can recapitulate the clinical features exhibited by patients, and thus help uncover a DOX-dependent pathomechanism. ACT-iPSC CM generated from individuals with CD20+ B-cell lymphoma who had received high doses of DOX and suffered cardiac dysfunction were studied and compared to control-iPSC CM from cancer survivors without cardiac symptoms. In cellular studies, ACT-iPSC CM were persistently more susceptible to DOX toxicity including augmented disorganized myofilament structure, changed mitochondrial shape, and increased apoptotic events. Consistently, ACT-iPSC CM and cardiac fibroblasts isolated from fibrotic human ACT myocardium exhibited higher DOX-dependent reactive oxygen species. In functional studies, Ca2+ transient amplitude of ACT-iPSC CM was reduced compared to control cells, and diastolic sarcoplasmic reticulum Ca2+ leak was DOX-dependently increased. This could be explained by overactive CaMKIIδ in ACT CM. Together with DOX-dependent augmented proarrhythmic cellular triggers and prolonged action potentials in ACT CM, this suggests a cellular link to arrhythmogenic events and contractile dysfunction especially found in ACT engineered human myocardium. CamKIIδ inhibition prevented proarrhythmic triggers in ACT. In contrast, control CM upregulated SERCA2a expression in a DOX-dependent manner, possibly to avoid heart failure conditions. In conclusion, we developed the first human patient-specific stem cell model of DOX-induced cardiac dysfunction from patients with B-cell lymphoma. Our results suggest that DOX-induced stress resulted in arrhythmogenic events associated with contractile dysfunction and finally in heart failure after persistent stress activation in ACT patients.
datePublished:2022-03-08T00:00:00Z
dateModified:2022-03-08T00:00:00Z
pageStart:1
pageEnd:24
license:http://creativecommons.org/licenses/by/4.0/
sameAs:https://doi.org/10.1007/s00395-022-00918-7
keywords:
Anthracyclin-induced cardiotoxicity (ACT)
Induced pluripotent stem cells (iPSC)
Cardiomyocytes
Cardiac fibroblasts
Heart failure
Doxorubicin
Cardiology
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name:Clinic for Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany
name:DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Göttingen, Germany
name:Institute of Pharmacology and Toxicology, Würzburg University, Würzburg, Germany
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