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Background: : Heart failure (HF) is a global pandemic most commonly caused by coronary artery disease. Despite coronary revascularization, the infarcted myocardium can develop into an irreversible scar toward chronic ischemic HF. This is due to the limited regenerative capacity of the adult human heart. Recently, the vascular cell adhesion molecule 1 positive cardiac fibroblast (VCF) has been shown to directly improve cardiac contractility in addition to promoting myocardial growth in preclinical studies. This clinical trial aims to explore the safety and, in part, the efficacy of autologous VCF therapy for chronic ischemic HF., Methods: : This first-in-human trial is an open-label, single-arm, phase 1 study conducted at a single center. This study will include 6 patients with chronic ischemic HF in stage C and NYHA class II or III despite receiving the standard of care, including coronary revascularization. Participants will undergo cardiac biopsy to manufacture autologous VCFs expressing CD90 and CD106. Under electro-anatomical mapping guidance, participants will receive a transendocardial injection of VCF in a modified 3 + 3 design. The first 3 patients will receive a standard dose (2 × 107 cells) of VCF with a 4-week interval for safety assessment before subsequent enrollment. In the absence of safety issues, the final 3 patients will receive the standard dose of VCF without a 4-week interval. In the presence of safety issues, the final 3 patients will receive a reduced dose (1.5 × 107 cells) of VCF with the 4-week interval., Discussion: This is the first clinical study of cardiac regeneration using VCFs for the treatment of chronic ischemic HF. The study results will contribute to the development of a minimally invasive cell therapy for patients with HF failed by the standard of care., Trial Registration: This study was registered with the Japan Registry of Clinical Trials (jRCT2033210078)., Competing Interests: The remaining authors declare no conflict of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)