The intrinsic cardiac nervous system comprises two molecularly and functionally distinct neuron subtypes—Npy+ neurons that function as parasympathetic postganglionic cells essential for maintaining coronary perfusion through active regulation of aortic root mechanics during baseline conditions, and Ddah1+ neurons that preserve cardiac electrical stability and prevent sudden death during extreme stress—revealing a division of labor within the cardiac neural network that supports both routine homeostasis and stress resilience.

The intrinsic cardiac nervous system (ICNS), often referred to as “the little brain on the heart”, plays a central role in heart-brain communication and is increasingly recognized as both a contributor to cardiac disorders, including atrial fibrillation, heart failure, and sudden cardiac death, and a growing target for therapeutic intervention. Despite its clinical relevance, the molecular and functional organization of the ICNS remains poorly understood. Using single-cell transcriptomics, high-resolution imaging, and cell-specific genetic tools in mice, we identified two molecularly distinct intrinsic cardiac neuron (ICN) subtypes marked by Npy and Ddah1, each exhibiting unique anatomical innervation patterns. Npy⁺ ICNs function as parasympathetic postganglionic neurons essential for maintaining coronary perfusion and cardiac homeostasis during routine physiological activity. In contrast, Ddah1⁺ ICNs are crucial for preserving cardiac electrical stability and preventing sudden death under extreme stress. These findings uncover specialized ICNS pathways that support cardiac homeostasis and resilience, providing a foundation for developing targeted neurocardiac therapies for autonomic dysfunction in human heart disease.