Heart failure in cancer: role of checkpoint inhibitors

Delgobo, Murilo; Frantz, Stefan

doi:10.21037/jtd.2018.10.07

Cited by 14 publications

(11 citation statements)

References 97 publications

(106 reference statements)

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“…Consequently, the appearance of a new or progressing pericardial effusion may increase the possibility of anti-PD-1/PDL-1-related perimyocarditis but should not be regarded as a separate condition from other findings. In terms of histology, numerous studies indicated that immune checkpoint treatment is accompanied by acute fibrinous pericarditis with mixed inflammatory infiltrations in the pericardial wall and the deposition of surface fibrins [45] .…”

Section: Etiologymentioning

confidence: 99%

“…The presence of dilated cardiopathy without edema (FDG PET/MRI) or with increased troponin markers during treatment with PD-1/PDL-1 inhibitors indicates the existence of non-inflammatory left ventricular dysfunction [47] . One interesting study reported that the reduction of PD-1 expression resulted in dilated cardiomyopathy with severely impaired contraction and congestive heart failure, which resulted in sudden death [45] . PDL-1 expression on cardiomyocytes is upregulated in cardiac diseases such as ischemia–reperfusion injury and left ventricular hypertrophy in preclinical studies [27] .…”

Section: Etiologymentioning

confidence: 99%

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PD-1/PDL-1 Inhibitors and Cardiotoxicity; Molecular, Etiological and Management Outlines

Safi

Ahmed

Al‐Azab

et al. 2021

Journal of Advanced Research

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Section: Etiologymentioning

confidence: 99%

Section: Etiologymentioning

confidence: 99%

PD-1/PDL-1 Inhibitors and Cardiotoxicity; Molecular, Etiological and Management Outlines

Safi

Ahmed

Al‐Azab

et al. 2021

Journal of Advanced Research

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“…PD-L1 is expressed on a wide range of non-hematopoietic cells, including murine and human heart [6,8,9], and thus the PD-1/PD-L1 regulatory system is crucial in maintaining peripheral tolerance [10]. PD-1/PD-L1 plays a pivotal role in regulating cytotoxic T-lymphocyte and effector T-helper cell activities to prevent autoimmune myocarditis [11]. Cardiotoxicity can be happening when PD-1/PD-L1 is interrupted.…”

Section: Introductionmentioning

confidence: 99%

Programmed Cell Death-1: Programmed Cell Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response In Vitro

Tay

Fang

Beh

et al. 2020

IJMS

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Aim: Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro. Methods and Results: We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4+ T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8+ T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4+ and CD8+ T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly. Conclusion: PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes.

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“…The patient’s Troponin I levels were 13 times higher than the normal, and myocardial biopsy revealed fibrosis with inflammation infiltrated by CD8+T cells. Myocarditis is also considered to be the earliest cardiotoxic reaction, occurring on average 17 days after initial treatment ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Risk of Cardiac Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-Analysis

Tian

et al. 2021

Front. Oncol.

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BackgroundWe performed a systematic review and meta-analysis to evaluate the risks of cardiac adverse events in solid tumor patients treated with monotherapy of immune checkpoint inhibitors (ICIs) or combined therapy of ICIs plus chemotherapy.MethodsEligible studies were selected through the following databases: PubMed, Embase and clinical trials (https://clinicaltrials.gov.) and included phase III/IV randomized controlled trials (RCTs) involving patients with the solid tumor treated with ICIs. The data was analyzed by using Review Manager (version5.3), Stata (version 15.1).ResultsAmong 2,551 studies, 25 clinical trials including 20,244 patients were qualified for the meta-analysis. Compared with PD-1 inhibitor (nivolumab) or CTLA-4 inhibitor (ipilimumab), PD-1 inhibitor (nivolumab) plus CTLA-4 inhibitor (ipilimumab) combined therapy showed significant increase in grade 5 arrhythmology (OR 3.90, 95% CI: 1.08–14.06, p = 0.603). PD-1 inhibitor plus chemotherapy show significant increase in grades 1–5 myocardial disease (OR 5.09, 95% CI: 1.11–23.32, p = 1.000). Compared with chemotherapy, PD-1 inhibitor (nivolumab) or CTLA-4 inhibitor (ipilimumab), PD-1 inhibitor (nivolumab) plus CTLA-4 inhibitor (ipilimumab) combined therapy show significant increase in grades 1–5 arrhythmology (OR 2.49, 95% CI: 1.30–4.78, p = 0.289).ConclusionsOur meta-analysis demonstrated that PD-1 inhibitor plus CTLA-4 inhibitor can result in a higher risk of grade 5 arrhythmology in comparison with PD-1/CTLA-4 inhibitor alone, and a higher risk of grade 5 arrhythmology in comparison with chemotherapy. PD-1 inhibitor plus chemotherapy treatment could increase the risk of all-grade myocardial disease compared with chemotherapy. However, in most cases, there was no significant increase of risks of cardiovascular toxicity in PD-1/PD-L1 inhibitor monotherapy or PD-1/PD-L1 inhibitor plus chemotherapy compared with chemotherapy alone.

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Heart failure in cancer: role of checkpoint inhibitors

Cited by 14 publications

References 97 publications

PD-1/PDL-1 Inhibitors and Cardiotoxicity; Molecular, Etiological and Management Outlines

PD-1/PDL-1 Inhibitors and Cardiotoxicity; Molecular, Etiological and Management Outlines

Programmed Cell Death-1: Programmed Cell Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response In Vitro

Risk of Cardiac Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-Analysis

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