A Developmental Mechanism Linking Heart Evolution and Congenital Defects

AbstractThe evolution of double circulation in vertebrates required precise remodeling of the embryonic outflow tract (OFT), but the mechanisms enabling this transition remain unclear. Here, we show that oxygen acts as a developmental switch regulating apoptosis during OFT septation. In chick embryos, transient hypoxia disrupts apoptosis and produces atavistic phenotypes resembling ancestral vertebrate hearts with a single circulation. Comparative evidence suggests that developmental mode and associated oxygen levels facilitated OFT septation and the evolution of double circulation. This oxygen dependence also explains why CHD risk is elevated in hypoxic conditions, such as high-altitude pregnancy and maternal cardiovascular disease. Our findings establish a mechanistic link between heart development, evolution, and congenital defects, highlighting oxygen as both a driver of innovation and a source of vulnerability. This work challenges traditional views of cardiogenesis and underscores the need for integrative approaches to heart development and disease.SummaryThe evolution of warm-bloodedness in birds and mammals required profound physiological innovations, including a four-chambered heart with separate pulmonary and systemic circulation. This restructuring allowed for more efficient oxygen transport, supporting the high metabolic demands of sustained activity. While the anatomical and functional advantages of this transition are well understood, the developmental mechanisms that enabled it remain unclear. Here, we propose that changes in embryonic oxygen availability directly shaped the evolution of heart structure. We show that oxygen levels regulate programmed cell death during the remodeling of the heart’s outflow tract, a critical process in the formation of separate circulatory circuits. Experimentally reducing oxygen in developing chick embryos prevented this programmed cell death, disrupted heart remodeling, and produced ancestral-like cardiac structures resembling those of cold-blooded vertebrates. These findings provide a developmental mechanism linking oxygen availability to heart evolution, explaining how changes in embryonic environment could have facilitated the transition to double circulation. They also suggest that congenital heart defects arise when this oxygen-sensitive developmental process is disrupted, offering new insights into why some heart malformations resemble ancestral states. By identifying oxygen as a key environmental cue in heart development, our study underscores the importance of non-genetic factors in shaping evolutionary transitions.