ICIs-Related Cardiotoxicity in Different Types of Cancer

Dong, Mei; Yu, Ting; Zhang, Zhenzhen; Zhang, Jing; Wang, Rujian; Tse, Gary; Liu, Tong; Zou, Lin

doi:10.3390/jcdd9070203

Cited by 13 publications

(9 citation statements)

References 104 publications

(116 reference statements)

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“…Cardiovascular complications in cancer patients treated with ICIs include fatal myocarditis, vasculitis, arrhythmia, fibrosis and heart failure (7,8). In different types of cancer, different ICIs may show different cardiotoxicity spectra (9). The incidence of ICIs-related cardiovascular events ranged from 0.15 to 10%.…”

Section: Introductionmentioning

confidence: 99%

“…The incidence of ICIs-related cardiovascular events ranged from 0.15 to 10%. For example, in melanomas, PD-1/PD-L1 inhibitor use was closely related to high blood pressure and myocarditis (8,9). Lung cancer patients, commonly experienced acute coronary syndrome, arrhythmia and heart failure (9).…”

Section: Introductionmentioning

confidence: 99%

“…For example, in melanomas, PD-1/PD-L1 inhibitor use was closely related to high blood pressure and myocarditis (8,9). Lung cancer patients, commonly experienced acute coronary syndrome, arrhythmia and heart failure (9). The most common cardiotoxic events after nivolumab and pembrolizumab therapy in lung cancer patients are arrhythmia, cardiac-related chest pain, cardiomyopathy, and myopericardial diseases.…”

Section: Introductionmentioning

confidence: 99%

“…The most common cardiotoxic events after nivolumab and pembrolizumab therapy in lung cancer patients are arrhythmia, cardiac-related chest pain, cardiomyopathy, and myopericardial diseases. Moreover, renal cell carcinomas patients treated with nivolumab associated to ipilimumab frequently experienced hypertension (9); patients with urothelial carcinoma treated with atezolizumab had frequently hypertension and arrhythmia. Therefore, a complex interaction between cancer-related and immune-related factors plays a key role in pathogenesis of cardiovascular toxicities.…”

Section: Introductionmentioning

confidence: 99%

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Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, galectine-3, and NLRP3-MyD88-chemokine pathways

Quagliariello

Passariello

Mauro

et al. 2022

Front. Cardiovasc. Med.

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BackgroundImmune checkpoint inhibitors (ICIs) have significantly changed the oncology clinic in recent years, improving survival expectations in cancer patients. ICI therapy have a broad spectrum of side effects from endocrinopathies to cardiovascular diseases. In this study, pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models were analyzed.MethodsFirstly, in a human in vitro model, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (with CTLA-4 or PD-1 blocking agents, at 200 nM) for 72 h. After treatment, production of DAMPs and 12 cytokines were analyzed in the supernatant through colorimetric and enzymatic assays. C57/Bl6 mice were treated with CTLA-4 or PD-1 blocking agents (15 mg/kg) for 10 days. Before (T0), after three days (T3) and after treatments (T10), ejection fraction, fractional shortening, radial and longitudinal strain were calculated by using bidimensional echocardiography (Vevo 2100, Fujfilm). Fibrosis, necrosis, hypertrophy and vascular NF-kB expression were analyzed through Immunohistochemistry. Myocardial expression of DAMPs (S100- Calgranulin, Fibronectin and Galectine-3), MyD88, NLRP3 and twelve cytokines have been analyzed. Systemic levels of SDF-1, IL-1β, and IL-6 were analyzed before, during and after ICIs therapy.ResultsRadial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. No myocardial hypertrophy was seen with the exception of the pembrolizumab group. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 inflammasome and MyD88 and induced both in vitro and in vivo the secretion of IL-1β, TNF-α and IL-6. Systemic levels of SDF-1, IL-1β and IL-6 were increased during and after treatment with ICIs.ConclusionsShort therapy with PD-1 and CTLA-4 blocking agents increases vascular expression of NF-kB, systemic SDF-1, IL-1β, IL-6 levels and myocardial NLRP3, MyD88 and DAMPs expression in preclinical models. A pro-inflammatory cytokine storm was induced in myocardial tissues and in cultured cardiac cells after ICIs therapy. The overall picture of the study suggests new putative biomarkers of ICIs-mediated systemic and myocardial damages potentially useful in clinical cardioncology.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, galectine-3, and NLRP3-MyD88-chemokine pathways

Quagliariello

Passariello

Mauro

et al. 2022

Front. Cardiovasc. Med.

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“…Owing to the autoimmune nature of these events, they may affect a wide range of organ systems, resulting in cutaneous, gastrointestinal, pulmonary, hepatic, neurological, cardiac, and endocrine manifestations 10–14 . As above mentioned, these include DM, 6,7,15,16 which, given its well‐known detrimental effects on multiple organ systems, may add substantially to the morbidity of patients using ICIs.…”

Section: Introductionmentioning

confidence: 99%

Risk of diabetes mellitus among users of immune checkpoint inhibitors: A population‐based cohort study

Chan¹,

Lee²,

Kong³

et al. 2023

Cancer Medicine

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Prognostic value of cardiovascular magnetic resonance in immune checkpoint inhibitor‐associated myocarditis: A systematic review and meta‐analysis

Song,

Zhang,

et al. 2024

Cancer Innovation

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BackgroundImmune checkpoint inhibitors (ICI) are increasingly used in the first‐line treatment of malignant tumors. There is increasing recognition of their cardiotoxicity and, in particular, their potential to lead to myocarditis. Cardiovascular magnetic resonance (CMR) can quantify pathological changes, such as myocardial edema and fibrosis. The purpose of this systematic review and meta‐analysis was to examine the evidence for the roles of CMR in predicting prognosis in ICI‐associated myocarditis.MethodsPubMed, Cochrane Library, and Web of Science databases were searched until October 2023 for published works investigating the relationship between CMR parameters and adverse events in patients with ICI‐associated myocarditis. The analysis included studies reporting the incidence of late gadolinium enhancement (LGE), T1 values, T2 values, and CMR‐derived left ventricular ejection fraction (LVEF). Odds ratios (OR) and weighted mean differences (WMD) were combined for binary and continuous data, respectively. Newcastle‐Ottawa Scale was used to assess the methodological quality of the included studies.ResultsFive cohort studies were included (average age 65–68 years; 25.4% female). Of these, four studies were included in the meta‐analysis of LGE‐related findings. Patients with major adverse cardiovascular events (MACE) had a higher incidence of LGE compared with patients without MACE (OR = 4.18, 95% CI: 1.72–10.19, p = 0.002). A meta‐analysis, incorporating data from two studies, showed that patients who developed MACE exhibited significantly higher T1 value (WMD = 36.16 ms, 95% CI: 21.43–50.89, p < 0.001) and lower LVEF (WMD = − 8.00%, 95% CI: −13.60 to −2.40, p = 0.005). Notably, T2 value (WMD = −0.23 ms, 95% CI: −1.86 to −1.39, p = 0.779) was not associated with MACE in patients with ICI‐related myocarditis.ConclusionsLGE, T1 value, and LVEF measured by CMR imaging have potential prognostic value for long‐term adverse events in patients with ICI‐related myocarditis.

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ICIs-Related Cardiotoxicity in Different Types of Cancer

Cited by 13 publications

References 104 publications

Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, galectine-3, and NLRP3-MyD88-chemokine pathways

Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, galectine-3, and NLRP3-MyD88-chemokine pathways

Risk of diabetes mellitus among users of immune checkpoint inhibitors: A population‐based cohort study

Prognostic value of cardiovascular magnetic resonance in immune checkpoint inhibitor‐associated myocarditis: A systematic review and meta‐analysis

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