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Background: The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure., Methods: Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes., Results: Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction-induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload., Conclusions: Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure., Competing Interests: The Department of Health Development and Medicine in Osaka University (H.H, H.N) is an endowed department supported by Anges, Daicel, and FunPep. The other authors report no conflicts.

Although clonal hematopoiesis of indeterminate potential (CHIP) is an adverse prognostic factor for atherosclerotic disease, its impact on nonischemic dilated cardiomyopathy (DCM) is elusive. The authors performed whole-exome sequencing and deep target sequencing among 198 patients with DCM and detected germline mutations in cardiomyopathy-related genes and somatic mutations in CHIP driver genes. Twenty-five CHIP driver mutations were detected in 22 patients with DCM. Ninety-two patients had cardiomyopathy-related pathogenic mutations. Multivariable analysis revealed that CHIP was an independent risk factor of left ventricular reverse remodeling, irrespective of known prognostic factors. CHIP exacerbated cardiac systolic dysfunction and fibrosis in a DCM murine model. The identification of germline and somatic mutations in patients with DCM predicts clinical prognosis., Competing Interests: This work was supported by grants from the SENSHIN Medical Research Foundation (to Dr Nomura), the Japan Foundation for Applied Enzymology (to Drs Ko, Nomura, and Dai), the Kanae Foundation for the Promotion of Medical Science (to Dr Nomura), the MSD Life Science Foundation (to Dr Nomura), the Sakakibara Heart Foundation Cardiovascular Research Program 2023 (to Dr Ko), the Tokyo Biomedical Research Foundation (to Dr Nomura), the Astellas Foundation for Research on Metabolic Disorders (to Dr Nomura), the Novartis Foundation (Japan) for the Promotion of Science (to Dr Nomura), the Japanese Circulation Society (to Drs Ko and Nomura), the Takeda Science Foundation (to Drs Ko and Nomura), the Cell Science Research Foundation (to Dr Nomura), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Dr Nomura), the Japan Heart Foundation (to Dr Ko), and the Daiichi-Sankyo Foundation of Life Science (to Dr Nomura); a Grant-in-Aid for Scientific Research (A) (to Dr Nomura); a Grant-in-Aid for Scientific Research (S) (to Dr Komuro); the UTEC-UTokyo FSI Research Grant Program (to Dr Nomura); the JST FOREST Program (grant JPMJFR210U) (to Dr Nomura); a Japan Society for the Promotion of Science Grant-in-Aid for Japan Society for the Promotion of Science fellow (23KJ0434) (to Dr Dai) and AMED JP23ek0109600h0002 (to Dr Ko); and JP20ek0109487, JP18km0405209, JP21ek0109543, JP21tm0724601, JP22ama121016, JP22ek0210172, JP22ek0210167, JP22bm1123011, JP23tm0724607, JP23gm4010020, JP23tm0524009, JP23tm0524004, JP23jf0126003, and JP24ek0109755 (to Drs Nomura and Komuro). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Reliable predictors of treatment efficacy in heart failure have been long awaited. DNA damage has been implicated as a cause of heart failure., Objectives: The purpose of this study was to investigate the association of DNA damage in myocardial tissue with treatment response and prognosis of heart failure., Methods: The authors performed immunostaining of DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in endomyocardial biopsy specimens from 175 patients with heart failure with reduced ejection fraction (HFrEF) of various underlying etiologies. They calculated the percentage of nuclei positive for each DNA damage marker (%PAR and %γ-H2A.X). The primary outcome was left ventricular reverse remodeling (LVRR) at 1 year, and the secondary outcome was a composite of cardiovascular death, heart transplantation, and ventricular assist device implantation., Results: Patients who did not achieve LVRR after the optimization of medical therapies presented with significantly higher %PAR and %γ-H2A.X. The ROC analysis demonstrated good performance of both %PAR and %γ-H2A.X for predicting LVRR (AUCs: 0.867 and 0.855, respectively). There was a negative correlation between the mean proportion of DNA damage marker-positive nuclei and the probability of LVRR across different underlying diseases. In addition, patients with higher %PAR or %γ-H2A.X had more long-term clinical events (PAR HR: 1.63 [95% CI: 1.31-2.01]; P < 0.001; γ-H2A.X HR: 1.48 [95% CI: 1.27-1.72]; P < 0.001)., Conclusions: DNA damage determines the consequences of human heart failure. Assessment of DNA damage is useful to predict treatment efficacy and prognosis of heart failure patients with various underlying etiologies., Competing Interests: Funding Support and Author Disclosures This work was supported by a Japan Society for the Promotion Science (JSPS) Grant-in-Aid for Scientific Research (A) (to Dr Nomura), a JSPS Grant-in-Aid for Scientific Research (S) (to Dr Komuro), a JSPS Grant-in-Aid for JSPS fellows (grant number 23KJ0434 to Dr Dai), the UTEC-UTokyo FSI Research Grant Program (to Dr Nomura), JST FOREST Program (grant number JPMJFR210U to Dr Nomura), Japan Foundation for Applied Enzymology (to Drs Ko and Dai), SENSHIN Medical Research Foundation (to Dr Ko), Merck Sharp & Dohme Life Science Foundation (to Dr Ko), Takeda Science Foundation (to Dr Ko), Japanese Circulation Society (to Dr Ko), Japan Heart Foundation (to Dr Ko), Sakakibara Heart Foundation Cardiovascular Research Program 2023 (to Dr Ko), and Japan Agency for Medical Research and Development (AMED) (grant nos. 22ek0109600h0002 to Dr Ko and JP20ek0210141, JP20ek0109487, JP17gm0810013, JP18km0405209, JP19ek0210118, JP21ek0109543, and JP21ek0109569 to Drs Nomura and Komuro). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)