TY - JOUR
T1 - Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients
AU - Haupt, Luis Peter
AU - Rebs, Sabine
AU - Maurer, Wiebke
AU - Hübscher, Daniela
AU - Tiburcy, Malte
AU - Pabel, Steffen
AU - Maus, Andreas
AU - Köhne, Steffen
AU - Tappu, Rewati
AU - Haas, Jan
AU - Li, Yun
AU - Sasse, Andre
AU - Santos, Celio C.X.
AU - Dressel, Ralf
AU - Wojnowski, Leszek
AU - Bunt, Gertrude
AU - Möbius, Wiebke
AU - Shah, Ajay M.
AU - Meder, Benjamin
AU - Wollnik, Bernd
AU - Sossalla, Samuel
AU - Hasenfuss, Gerd
AU - Streckfuss-Bömeke, Katrin
N1 - Funding Information:
The authors thank Sandra Georgi, Carmen Klopper, Johanna Heine, Yvonne Metz, and Timo Schulte for excellent technical assistance; Torben Ruhwedel and Boguslawa Sadowski (MPI-NAT) for excellent technical assistance in the electron microscopic analysis; Dr. Alexander Becker and all others who helped collect skin punch biopsies from patients with ACT and control subjects, and Hanibal Bohnenberger for organizing hematoxylin and eosin staining of human cardiac tissue slices in the Department of Pathology, University Medicine Göttingen. We thank Ms. Marita Ziepert for providing the information on the ACT patients from the RICOVER60 study as a prerequisite for choosing the ACT patient in this study. In addition, we thank Cynthia Bunker and Gabriela Lobo for proofreading.
Funding Information:
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Bundesministerium für Bildung und Forschung (BMBF) grant e:Bio – Modul II – Verbundprojekt: CaRNAtion [031L0075C to KSB and GH], the German Center for Cardiovascular Research (DZHK) [B14031KSB to KSB, MT, and BM], the Heidenreich von Siebold Program from the University Medical Center Göttingen (KSB), the German Heart Foundation/German Foundation of Heart Research [AZ. F/38/18] (to KSB), the Else Kröner-Fresenius-Stiftung Foundation [2017-A137] (to KSB and SS), and the Informatics for Life, Klaus Tschira Stiftung as well as the Detectin HF, ERA-CVD (to BM). SP is funded by the German Society of Internal Medicine. AM, SK, and WM are fellows of the International Research Training Group 1816 funded by the Deutsche Forschungsgemeinschaft. AMS is supported by the British Heart Foundation and in part by the Department of Health via a National Institute for Health Research (NIHR) Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. WM is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC 2067/1- 390729940.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Anthracyclin-induced cardiotoxicity (ACT)
KW - Cardiac fibroblasts
KW - Cardiomyocytes
KW - Doxorubicin
KW - Heart failure
KW - Induced pluripotent stem cells (iPSC)
UR - http://www.scopus.com/inward/record.url?scp=85126081018&partnerID=8YFLogxK
U2 - 10.1007/s00395-022-00918-7
DO - 10.1007/s00395-022-00918-7
M3 - Article
C2 - 35260914
AN - SCOPUS:85126081018
SN - 0300-8428
VL - 117
JO - Basic Research in Cardiology
JF - Basic Research in Cardiology
IS - 1
M1 - 13
ER -
