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Single-cell genomics has emerged as a transformative approach to unravel the complexity of somatic variation in specific cells within the human body. This field has profound implications for understanding the role of somatic mutations in aging, cardiovascular disease, and tissue-specific pathologies. By focusing on circulating cells and cardiac resident cells, including cardiomyocytes, within the heart, this review explores how single-cell genomics provides insights into cellular heterogeneity and clonal evolution. We discuss the implications of somatic variation for cardiovascular health, highlight technological innovation, and future directions in this rapidly evolving field. This review sheds light on national initiatives, such as the National Institutes of Health Somatic Mosaicism Across Human Tissues Network (SMaHT) and the European Somatic Mutations in Vascular-Wall Function and Age-Associated Disease (EU SOMATICART) project, which aim to generate reference atlases of somatic mutations across human tissues. It also explores challenges and future directions in leveraging single-cell approaches to improve diagnostics and therapeutics in cardiovascular disease.