Deciphering the cardiac neuron landscape in heart failure patients

Neurons exert a pivotal role in the preservation of cardiac physiological function. However, there is a lack of explanation about the mechanism of cardiac neurons in the pathogenesis of cardiac dysfunction. Here, we generated a cardiac neuron landscape including 11,026 neuronal cells based on the integration of published single-nucleus RNA sequencing data from 75 patients with heart failure and 45 healthy donors. We determined ten distinct neuronal cell subsets differing in abundances, compositions, and biological functions in the heart. In particular, N4-ALK neurons were significantly enriched in failing hearts relative to healthy controls, and their abundance was associated with the response to left ventricular assist device implantation. RXRG, a transcription factor highly expressed in neuronal cells, participated in the transcriptional regulatory network of N4-ALK neurons and showed a positive correlation with the expression of their marker genes. Notably, in heart failure, the PTN-PTPRZ1 axis mediated specific crosstalk between cardiac fibroblasts and N4-ALK neurons. Finally, we used N4-ALK-related features to develop an optimized prediction model for identifying individuals with heart failure. Overall, our integrative cardiac neuron atlas comprehensively characterizes the molecular and functional diversity of neuronal cells, providing a new perspective for further exploration of the regulatory function of neurons in heart failure.