The intrinsic cardiac nervous system is essential for cardiac function and survival

The intrinsic cardiac nervous system (ICNS) is a key node in heart-brain communication and an emerging target for cardiac therapy, yet its physiological importance and functional organization remain poorly understood. Here, we show that the ICNS is essential for cardiac performance and survival across conditions. Using integrated genetic and imaging approaches in mice, we identify two molecularly distinct intrinsic cardiac neuron (ICN) subtypes that differ in extrinsic inputs, projection architectures, and physiological roles. Npy⁺ ICNs preferentially receive vagal input and mediate parasympathetic control of heart rate and coronary perfusion, and their ablation leads to fatal cardiac failure. By contrast, Ddah1⁺ ICNs receive sympathetic input and are required to preserve electrical stability and prevent sudden cardiac arrest under extreme physiological or psychological stress, with their activation providing cardioprotection. Together, these findings establish the ICNS as a critical regulator of cardiac function, providing a framework for precise, cell-type-targeted neuromodulatory therapies.