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Background and Purpose: Immune checkpoint inhibitors (ICI), such as anti‐PD‐1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T‐cells against tumours. However, enhanced T‐cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI‐induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD‐1 inhibition on cardiac function and explore the molecular mechanisms of ICI‐induced cardiotoxicity. Experimental Approach: C57BL6/J and BALB/c mice were treated with isotype control or anti‐PD‐1 antibody. Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT‐PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow‐up experiments, anti‐CD4 and anti‐IL‐17A antibodies were used along with PD‐1 blockade in C57BL/6J mice. Key Results: Anti‐PD‐1 treatment led to cardiac dysfunction and left ventricular dilation in C57BL/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD‐1 inhibition resulted in enhanced thymic inflammatory signalling, where Il17a increased most prominently. In BALB/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL‐17A prevented anti‐PD‐1‐induced cardiac dysfunction in C57BL6/J mice. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, and Ldb3) were revealed, related to cardiac structure, signalling, and inflammation. Conclusions: PD‐1 blockade induces cardiac dysfunction in mice with increased IL‐17 signalling in the thymus. Pharmacological inhibition of IL‐17A treatment prevents ICI‐induced cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Aims: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of death worldwide; thus, therapeutic improvements are needed. In vivo preclinical models are essential to identify molecular drug targets for future therapies. Transverse aortic constriction (TAC) is a well-established model of HFrEF; however, highly experienced personnel are needed for the surgery, and several weeks of follow-up are necessary to develop HFrEF. To this end, we aimed (i) to develop an easy-to-perform mouse model of HFrEF by treating Balb/c mice with angiotensin-II (Ang-II) for 2 weeks by minipump and (ii) to compare its cardiac phenotype and transcriptome to the well-established TAC model of HFrEF in C57BL/6J mice., Methods: Mortality and gross pathological data, cardiac structural and functional characteristics assessed by echocardiography and immunohistochemistry and differential gene expression obtained by RNA-sequencing and gene-ontology analyses were used to characterize and compare the two models. To achieve statistical comparability between the two models, changes in treatment groups related to the corresponding control were compared (ΔTAC vs. ΔAng-II)., Results: Compared with the well-established TAC model, chronic Ang-II treatment of Balb/c mice shares similarities in cardiac systolic functional decline (left ventricular ejection fraction: -57.25 ± 7.17% vs. -43.68 ± 5.31% in ΔTAC vs. ΔAng-II; P = 0.1794) but shows a lesser degree of left ventricular dilation (left ventricular end-systolic volume: 190.81 ± 44.13 vs. 57.37 ± 10.18 mL in ΔTAC vs. ΔAng-II; P = 0.0252) and hypertrophy (cell surface area: 58.44 ± 6.1 vs. 10.24 ± 2.87 μm 2 in ΔTAC vs. ΔAng-II; P < 0.001); nevertheless, transcriptomic changes in the two HFrEF models show strong correlation (Spearman's r = 0.727; P < 0.001). In return, Ang-II treatment in Balb/c mice needs significantly less procedural time [38 min, interquartile range (IQR): 31-46 min in TAC vs. 6 min, IQR: 6-7 min in Ang-II; P < 0.001] and surgical expertise, is less of an object for peri-procedural mortality (15.8% in TAC vs. 0% in Ang-II; P = 0.105) and needs significantly shorter follow-up for developing HFrEF., Conclusions: Here, we demonstrate for the first time that chronic Ang-II treatment of Balb/c mice is also a relevant, reliable but significantly easier-to-perform preclinical model to identify novel pathomechanisms and targets in future HFrEF research., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)