Two Specialized Intrinsic Cardiac Neuron Types Safeguard Heart Homeostasis and Stress Resilience

Abstract 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.